Heterotrimeric G-proteins are components of the signal transduction pathways for the soluble and cell-contact signals that regulate normal growth and differentiation. There is now a greater appreciation of the role of the Gbetagamma-dimer in the regulation of a variety of intracellular effectors, including ion channels, adenylyl cyclase, and phospholipase Cbeta. In many cases, Gbetagamma-dimers are required for the activation of mitogen activated protein kinase (MAPK) pathways that promote cellular proliferation, although the underlying mechanisms have yet to be fully elucidated. Activation of phosphotidylinositol-3-kinase (PI3K) is a critical step in the intracellular transduction of survival signals. Gbetagamma-dimers directly activate PI3Kgamma as well as the more widely distributed PI3Kbeta. The activation of PI3Kgamma by Gbetagamma-dimers likely involves direct binding of specific Gbetagamma-dimers to both subunits of PI3Kgamma. Thus, Gbetagamma-dimers transmit signals from numerous receptors to a variety of intracellular effectors in distinct cellular contexts. Five distinct Gbeta-subunits and 12 distinct Ggamma-subunits have been identified. New experimental approaches are needed to elucidate the specific roles of individual Gbetagamma-dimers in the pathways that transduce signals for proliferation and survival.