It is Dr. Grace's first day, having turned down both Yale and the Mayo Clinic to work at the hospital where his father was a janitor. He fails to save the life of Caroline Patterson, a patient who was moved to a basement room by a suspicious orderly. Dr. Ryman Kreeger, a senior doctor who thinks the "Gemini Project" will let him live forever, is taken by the hospital's ghosts.

Kirstin Caine, a hit and run victim with spinal trauma is admitted to the hospital. Patrick has a setback, and becomes subject to the research of Dr. Stefani Volette, which involves killing Kirstin to treat Patrick. It is revealed that Patrick's paralysis was not from the accident, but instead induced by Volette as part of her research. The revelation leads to Volette herself becoming a subject in her own experiment.

Jordan Holland, son of Tremaine Holland and Alice Anne Holland, is admitted to the psychiatric ward after his father refuses to "turn him over" to the people behind the mysterious research. It is revealed that Jordan had died at birth, and was saved by Ambrosius to fulfill some destiny beginning on his 18th birthday. Tremaine fails to stop the plan, taking his own life before Jordan leaves with Ambrose.

Dr. Juan Antonio Marquez is flown in for special treatment at the same time that a John Doe is admitted. Marquez's one-of-a-kind blood infection quickly kills anyone else infected including his in-flight doctor, and All Souls' Nurse Cathy Cavalleri. It is revealed that John Doe is the real Juan Antonio Marquez, and that he was replaced by Colonel Avejo who tortured the real Marquez in prison. Avejo deliberately infects Marquez's niece who is saved with an immunity in the real Marquez's blood.

Barney Wheelock is almost killed, and has a near-death experience, just after being admitted. Dr. Elizabeth Baines, an old friend of Dr. Cullen, is at the hospital speaking on the "white light" near death experience. Wheelock becomes possessed by "Roger" and dangerous, kidnapping tattooed nurse Kim Peretti before killing his wife Calvette and their two sons. Roger then possesses Kim and goes after Dr. Sterling. It is revealed that "Roger" is an old "god of the dead" working through nurse Karen Waverly and has gone after Dr. Baines as the next victim. Dr. Cullen is attacked in the process, but saved by Dr. Grace.