After one short blind date, Mary Horowitz, a brilliant and eccentric crossword constructor, is convinced that Steve, a CCN cameraman, is her soul mate. Because his job takes him hither and yon, she crisscrosses the country following Steve, with the encouragement of a reporter, turning up at media events he's at to convince him they are perfect for each other. Along the way, she befriends an assortment of misfits who accept her for who she is, leading her to reassess her reasons for this strange journey.

In the unreal world of Sacred Heart Hospital, John "J.D." Dorian learns the ways of medicine, friendship and life.