Activated protein C (APC) proteolytically inactivates factors Va (FVa) and VIIIa (FVIIIa), which in turn control two key steps of the coagulation cascade. The pathophysiological importance of this anticoagulant mechanism is illustrated by the severe prothrombotic diathesis associated with the congenital deficiencies of protein C and its cofactor protein S. A poor anticoagulant response of plasma to APC (APC resistance) was first described in a thrombotic patient in 1993 and soon recognized as the most common risk factor for venous thrombosis. The underlying genetic defect was identified one year later as the FV Arg506Gln mutation (FV Leiden), which abolishes one of the APC-cleavage sites on FVa. These ground-breaking discoveries have stimulated numerous researches into the workings of the protein C pathway, the molecular mechanisms of APC resistance in carriers and noncarriers of FV Leiden, and the clinical significance of APC resistance. This chapter reviews the most important findings, summarizes the state of the art, and discusses new developments in this rapidly evolving research area.