Platelet‐derived growth factor (PDGF) and angiotensin II (All) are thought to mediate their biological effects in vascular smooth muscle cells (VSMCs) by causing alterations in cytosolic free calcium ([Ca2+]i). In this study we examine the pathways by which PDGF and All alter [Ca2 +]i in VSMCs. Addition of PDGF resulted in a rapid, transient, concentration‐dependent increase in [Ca2+]i; this rise in [Ca2 +]i was blocked completely by preincubation of cells with ethylene glycol‐bis (β‐aminoethyl ether) N,N,N′,N′‐tetraacetic acid (EGTA) or CoCl2, by the voltage‐sensitive Ca2 +‐channel antagonists verapamil or nifedipine, by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), or by pertussis toxin. All also caused an increase in [Ca2 +]i; however, All‐stimulated alterations in [Ca2+]i displayed different kinetics compared with those caused by PDGF. Pretreatment of cells with 8‐(diethylamine)‐octyl‐3,4,5‐trimethyoxybenzoate hydrochloride (TMB‐8), almost totally inhibited All‐induced increases in [Ca2+]i. EGTA or CoCl2 only slightly diminished All‐stimulated increases in [Ca2+]i. Nifedipine, verapamil, TPA, and pertussis toxin pretreatment were without effect on All‐induced increases in [Ca2+]i. PDGF and All both stimulated increases in total inositol phosphate accumulation, although the one‐half maximal concentration (ED50) for alterations in [Ca2+]i and phosphoinisitide hydrolysis differed by a factor of 10 for PDGF (3 × 10−10 M for Ca2+ vs. 2.5 × 10−9 M for phosphoinositide hydrolysis), but they were essentially identical for All (7.5 × 10−9 M for Ca2+ vs. 5.0 × 10−9 M for phosphoinositide hydrolysis). PDGF stimulated mitogenesis (as measured by [3H]‐thymidine incorporation into DNA) in VSMCs with an ED50 similar to that for PDGF‐induced alterations in phosphoinositide hydrolysis. PDGF‐stimulated mitogenesis was blocked by pretreatment of cells with voltage‐sensitive Ca2 + channel blockers, TPA, or pertussis toxin. These results suggest that PDGF and All cause alterations in [Ca2+]i in VSMCs by at least quantitatively distinct mechanisms. PDGF binding activates a pertussis‐toxin‐sensitive Ca2+ influx into cells via voltage‐sensitive Ca2+ channels (blocked by EGTA, verapamil, and nifedipine), as well as stimulating phosphoinositide hydrolysis leading to release of Ca2+ from intracellular stores. All‐induced alterations in [Ca2+]i are mainly the result of phosphoinositide hydrolysis and consequent entry of Ca2+ into the cytoplasm from intracellular stores. Our data also suggest that changes in [Ca2 +]i caused by PDGF are required for PDGF‐stimulated mitogenesis.