Heterotrimeric G proteins attached to the cell membrane convey signals from G protein-coupled receptors in response to stimulation by a number of hormones, neurotransmitters, chemokines, and pharmacological agents to intracellular signaling cascades. The heterotrimeric G proteins are also located in the cell interior, and receptor-independent mechanisms may elicit their activation. Thus, G proteins may possibly exert cellular functions other than acting as signaling transducers. There is also increasing evidence for roles in different diseases including infections, inflammation, neurological diseases, cardiovascular diseases, cancer, and endocrine disorders. This review describes characteristics of the heterotrimeric G proteins, evidence for their involvement in different diseases, and outlines some of the therapeutic options utilizing G protein targets.