GTPases (GTP hydrolases, GTP binding proteins) are a large family of enzymes that direct various cellular functions, including signal transduction, protein biosynthesis, cell division and transport of vesicles. They are molecular switches that cycle between two conformational states (Figure 1): the inactive guanosine-5'-diphosphate (GDP)-bound state and the active guanosine-5'-triphosphate (GTP)-bound-state. In the GTP-bound ‘on’ state GTPases bind effector proteins and generate cellular responses, until GTP hydrolysis returns the switch to the ‘off’ state. GTP binding and hydrolysis occur in the highly conserved G domain. GTPases are characterized by low intrinsic GDP-GTP exchange and GTP hydrolysis rates; thus, both processes need to be controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) in order for the molecular switch to occur at physiologically relevant rates. With few exceptions, GTPases are grouped into two main families: heterotrimeric G proteins and small GTPases. In this chapter, we will summarize the current state of knowledge about the role of this vast family of proteins in the regulation of platelet functional responses, with a particular focus on the tight functional interrelationship between the most studied members of the two families.