Rodbell was educated at the University of Washington where he gained his PhD in 1954. He first worked at the National Institute of Health, Bethesda, Maryland. In 1985 he was appointed Scientific Director of the National Institute for Environmental Health Sciences, North Carolina.

Rodbell attempted to show at the molecular level how cells respond to such chemical signals as hormones and neurotransmitters. It had been shown by Earl Sutherland in 1957 that hormones, also known as ‘first messengers’, do not actually penetrate into the cell but rather stimulate the production of aso-called second messenger, cAMP (cyclic adenosine monophosphate). But, Rodbell asked, how does the binding of a hormone to its receptor stimulate the production of cAMP?

The process proved to be quite complex. In the late 1960s Rodbell found that at least two other factors, referred to as an amplifier and a transducer, were essential. The first extra factor, the amplifier, was needed to initiate the production of cAMP. It was identified as the enzyme AC (adenylate cyclase), which converted the energy-rich molecule ATP (adenosine triphosphate) into the second messenger cAMP. For the second extra factor, the transducer, Rodbell found that no reaction would occur without the presence of a complex energy-rich molecule GTP (guanine triphosphate). The GTP reacted in some way with the AC to initiate cAMP production. If either were absent the cell simply would not respond to such external stimuli as insulin or adrenaline.

For his work on what later became known as G proteins, Rodbell shared the 1994 Nobel Prize for physiology or medicine with Alfred Gilman.