Heterotrimeric guanine nucleotide binding proteins (G-proteins) mediate the effects of numerous hormones, neurotransmitters or sensory stimuli by coupling their transmembranous receptors to various effectors like enzymes and ion channels. Changes in the activity of these effector molecules eventually lead to the regulation of multiple cellular functions ranging from short term regulatory processes like the control of secretion rates, muscle tonus or metabolic processes to long term effects like regulation of growth and differentiation. Heterotrimeric G-proteins play a pivotal role in this transmembrane signaling process as they take part in processing and sorting of incoming signals as well as in adjusting the sensitivity of the system. This review describes some of the new insights into the biological role of G-protein mediated signaling processes provided by the analysis of mice genetically engineered to lack distinct G-protein alpha-subunits.