Melissa George as Dr. Alexandra Panttiere, the new Chief Innovation Officer (CIO) of St. Matthew's hospital, a cutting edge research hospital. She has a very idiosyncratic personality, and is constantly dealing with demons from her past history at the hospital.

 Dave Annable as Dr. Pierce Harrison, Alex's boyfriend and fellow surgeon.

 Don Hany as Dr. Jessie Shane, chief of surgery at St. Matthews, and Alex's former mentor from when she interned at the hospital.

 Shelley Conn as Dr. Millicent Silvano, hospital administrator. She is a stickler for procedure and the rules, much to Alex's chagrin.

 D. L. Hughley as Dr. Myron Hackett, hospital psychiatris.

 Jamie Kennedy as Dr. Casey Callahan, a surgeon in the hospital.

 Maya Erskine as Nurse Ji-Sung.

 JLouis Mills as Dr. Forester, the resident anesthesiologist who is blind in one eye.

Joshua Leonard as Max Elliot, Alex's gay ex-husband.