The involvement of the small GTPase Rap1b in platelet integrin α₂β₁-dependent outside-in signaling was investigated. Platelet adhesion to 4 different specific ligands for integrin α₂β₁, monomeric collagen, decorin, and collagen-derived peptides CB8(II) and CB11(II), induced a robust and rapid activation of Rap1b. This process did not require secreted ADP or thromboxane A₂ production but was critically regulated by phospholipase C (PLC)–derived second messengers. Both Ca²⁺ and protein kinase C were found to organize independent but additive pathways for Rap1b activation downstream of integrin-α₂β₁, which were completely blocked by inhibition of PLC with U73122. Moreover, integrin α₂β₁ engagement failed to trigger Rap1b activation in murine platelets lacking CalDAG-GEFI, a guanine nucleotide exchange factor regulated by Ca²⁺ and diacylglycerol, despite normal phosphorylation and activation of PLCγ2. In addition, CalDAG-GEFI–deficient platelets showed defective integrin α₂β₁-dependent adhesion and spreading. We found that outside-in signaling through integrin α₂β₁ triggered inside-out activation of integrin α_IIbβ₃ and promoted fibrinogen binding. Similarly to Rap1b stimulation, this process occurred downstream of PLC activation and was dramatically impaired in murine platelets lacking the Rap1 exchange factor CalDAG-GEFI. These results demonstrate that Rap1b is an important element in integrin-dependent outside-in signaling during platelet adhesion and regulates the cross talk between adhesive receptors.