Stimulation of cells by a broad variety of agonists results in a coordinated activation of Ca2+-, Ras-, and Rac-dependent pathways, which have to synergize to yield the corresponding biological response. This synergy requires a dense net of mutually positive and negative regulatory mechanisms. These include Ca2+-mediated activation of guanine nucleotide exchange proteins, resulting in increased levels of GTP-charged Ras and/or Rac or inactivation of small GTPases by Ca2+-mediated activation of GTPase-activating enzymes. Likewise, Ras as well as Rac control regulatory mechanisms, resulting in increased or diminished levels of cytosolic-free Ca2+. The biochemical mechanisms underlying these effects are discussed, with special reference to regulation of Ca2+ signaling by Ras and Rac.