Andy and Jake are having a little get-together before work when a car crashes into a lamppost in front of them. Both doctors immediately detect the person in the car had been drinking. Harold meets a member of Rose's cancer support group. Jake checks up on the drunk guy in the hospital and ends up having a good talk with him. Reid has a discussion with his academic counsellor. Amy takes Hannah out to a restaurant where she meets with her college friends.

An eighteen-year-old girl wants Andy to check her for the breast cancer gene, as it runs in her family. The girl and her older sister (who already had cancer and a double mastectomy) go see Andy for the results. Bright and Hannah are out on a date when something happens to both of them, and they call Harold. Kyle doesn't want lessons from Ephram anymore, again.

Andy consults Josh Stein, who's studying to become a rabbi. Josh also helps Delia with her Bat Mitzvah. Ephram supports Kyle, as his father comes to town. Amy's professor talks to Harold about a medical procedure. Andy is trying to go on a date with someone he met over the internet, but he has to postpone multiple times.

Bright takes Ephram to one of the college keggers to help cheer him up for some reason, but Ephram ignores the girls who are flirting with him and the party as he's playing video games. Also, lonely Edna suffers a panic attack and is rushed to the hospital. Lastly, Delia grows more rebellious against her father. Harold and Rose consider adopting a child from Africa, but the process of it is a lot harder than they expected.

Andy is harassing Ephram for being in community college and Kyle is in the room. Amy bonds with a cool teacher at Colorado A&M. She goes to a meeting about a search for the new Provost with a few other women invited by her cool new teacher.

A very-much-in-love Ephram discovers that he has unwittingly become a "girlfriend" to Amy, but the friendship takes a turn for something more when a moment of intimacy leads to them waking up together the next morning. Meanwhile, Nina grows suspicious of Jake's recent strange behavior, which is further amplified when his brother, Brian (guest star Tom Parker), shows up unexpectedly. Delia takes up with the popular girls in school, which worries Andy. Also, Bright tries to rectify Hannah's low self-esteem issues. Lastly, Rose drops some startling news on Harold, which could drastically change their lives.

With Hannah leaving for Minnesota in a few days with her mother (guest star Jayne Brook, "Chicago Hope"), Bright and Amy find themselves taking the loss of their girlfriend and best friend, respectively, harder than even they expected. Jake sets out on a high-risk bike trip with his friend, Cliff (guest star Simon Rex), that takes a near fatal turn; Andy and Harold uncharacteristically decide to go skydiving after hearing of Jake's daredevil ways; and Reid (guest star Justin Baldoni) keeps his promise to Ephram and backs off from pursuing Amy, leaving her feeling all the more lonely.

Hannah's mother (guest star Jayne Brook, "Chicago Hope") pays an unexpected visit to Everwood to tell Hannah that her father has passed away. Elsewhere in Everwood, Ephram stifles his feelings for Amy while forced to watch her relationship with Reid (guest star Justin Baldoni) grow more serious; Andy advises a patient (guest star Keith David, "Crash") who desperately needs a kidney transplant, but refuses to accept one from his daughter (guest star Gina Ravera). Lastly, Bright is at a loss at how best to help Hannah through this difficult time.

Andy and Jake are in therapy together with a councillor as they have some issues to settle. Nina leaves them to debate.

Bright tries to invite Ephram on a camping trip along with his dad Harold and Andy, but Ephram is reluctant even though he and Andy are doing a bit better. Ephram eventually does go though. Also, while Amy is working to get a play together she is mortified that her signals towards Reif were way off in her attempt to pursue a relationship with him. But they do eventually kiss. Ephram meets Kyle's mother, Tracy and thanks Ephram for all he has done for him. She also sets insight on why Kyle is the way he is, which leaves Ephram more contented that Kyle is just like him. Jake treats a 40 year-old woman who has stress urinary incontinence - someone who keeps wetting themselves and having no control over it. Edna has been quite perplexed lately as Jake is opening up his private office more for surgical procedures and botox sessions.

Ephram is back in town and is giving piano lessons at ECC now. Ephram begins his piano tutor session with a 13 year-old Kyle Hunter who has a major attitude. He doesn't want to play the "classical crap" though. He wants to go to Julliard, which Ephram finds funny but isn't as amused when he insults him a lot on his Julliard past. Nevertheless, once Kyle starts playing he is extremely good and Ephram is intrigued.

As if adjusting to college life and the news that her secret crush, Reid (guest star Justin Baldoni), is gay weren't enough to handle, Amy learns that Ephram is going to be a regular fixture in her life now that he's moved in with Bright and Reid. Meanwhile, Andy, Nina and Jake attempt to move on with life after Nina decides which man she loves---which is Jake. Bright and Ephram take Hannah to a college party. Andy gets involved in a case dealing with 17-year old Ethan Harcourt who is on anti-depressants since his older brother's car accident and death, but now wants to be intimate with his current girlfriend. Although, the anti-depressants he is taking is causing erectile dysfunction for him and tries to coerce Andy in letting him have Viagra. Ethan wants to keep all of this a secret from his girlfriend and family who don't know about his situation. Andy wavers that he's too young but Ethan doesn't listen and purchases medication online that inevitably ends him up in the hospital after

Andy learns that Ephram has no intention of moving back home, while Bright invites Ephram to move in with him and Reid (Justin Baldoni). Meanwhile, Hannah (Sarah Drew) begins to worry about the long term possibilities for her relationship with Bright after he shares his "three dates and out" policy; Harold suspects Andy is up to something after he frequently goes missing from the office. Nina and Jake have the grand opening for their new restaurant, Sam's. Nina is having a hard time convincing Everwood patrons on her new restaurant politics as "Mama Joys" is officially gone. But Nina gets some help when a couple of celebrities walk in and like her new establishment. Lastly, Ephram and Amy finally confront the unspoken fate of their relationship.

The fourth season begins with a nice wedding of an unexpected couple and kiss at the airport for couple Bright and Hannah in Everwood. Nina finally chooses between the two men she loves - Andy and Jake while at Delia's behest. Amy develops a new friendship with college-age student Reid (guest-star Justin Bardoni) while waiting on her mother Rose at the hospital. Also, Amy and Rose find that Rose's cancer has driven them apart rather than brought them together. Bright flirts with a new girl who might become his roommate, but is more involved in knowing what girlfriend Hannah scribbled off the postcard that she sent to him. Lastly, Ephram makes an emotional return to Everwood just in time for an unexpected wedding.