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The game is divided into three modes of play: Challenges, choices and surgeries. The first two modes are explored through several types of mini-games that have to be achieved in a limited amount of time: Finding Strength, Setting Priorities, Forming Decisions, Digging Deep, Distancing Yourself, Powering Through, Seeking Focus, Matching Rhythm, Building Resolve, and Finding Comfort. They allow navigating through the characters psychological state and are mostly related to their personal lives.
As for surgeries, surgical interventions have to be achieved by the characters as surgeons. They're all divided in simple steps and go from vital signs check to coronary arteries bypass, including injections, sutures, diagnoses (which are in fact a memorizing activity forcing the player to remember pictograms), CT-scans, MRIs and X-rays' reading (searching for anomalies), blood suction, intubation, etc. Surgeries can be divided in two parts separated by mini-games.
Conform to the series' structure, the game is composed of scenes and acts within episodes. The same title card is used. Each time a choice, a challenge or a surgery isn't fulfilled within the range of time allowed, the player loses a heart. If all five hearts are lost, the scene has to be attempted over again. If you are lucky, you may sometimes get the Dragon's Fury ability, this costs 30mp (medical points) and restores all lost hearts. At the end of each scene, a ranking is given to the player, depending of the number of hearts remaining. Five rankings are possible, following the surgical hierarchy: Chief of Surgery, Attending, Chief Resident, Resident, and Intern.
The plot focuses on an outbreak of diphtheria in the hospital. Other sub-plotlines are included, such as Cristina seeking for a fellowship despite Derek's bad review before catching diphtheria, Alex hesitating between Lexie and Ava, and of course Derek and Meredith's relationship.
In addition to the show's Season 4 regular characters, which are all included in the story, new characters have been created exclusively for the video game, such as CDC (Center for Disease Control) Agent Damon Birger, introduced to control the diphtheria outbreak, and Nurse Vince Bennet, who has Cristina as a love-interest.
People have criticized this game for the simplicity of the Mini-Games, and not using the actors from the TV show. People have also called the graphics a cheap sims rip-off. Some people have even used the Wii version more than the PC due to the Wii controller giving the mini-games a little more harder feel.