Thiazolidinediones (TZDs) are synthetic ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma) but also elicit PPARgamma-independent effects, most notably activation of mitogen-activated protein kinases (MAPKs). Ciglitazone rapidly activates extracellular signal-regulated kinase (Erk) MAPK, an event requiring c-Src kinase-dependent epidermal growth factor receptor (EGFR) transactivation, whereas troglitazone only weakly activates Erk and does not induce EGFR transactivation; the mechanism underlying this difference remains unclear. In this study, both ciglitazone and troglitazone increased Src activation. Similar effects were observed with Delta2-derivatives of each TZD, compounds that bind PPARgamma but do not lead to its activation, further indicating a PPARgamma-independent mechanism. Neither EGFR kinase nor Pyk2 inhibition prevented Src activation; however, inhibition of Src kinase activity prevented Pyk2 activation. Intracellular calcium chelation blocks TZD-induced Pyk2 activation; here, Src activation by both TZDs and ciglitazone-induced EGFR transactivation were prevented by calcium chelation. Accordingly, both TZDs increased calcium concentrations from intracellular stores; however, only ciglitazone produced a secondary calcium influx in the presence of extracellular calcium. Removal of extracellular calcium or inhibition of capacitative calcium entry by 2-APB prevented ciglitazone-induced EGFR transactivation and Erk activation but did not affect upstream kinase signaling pathways. These results demonstrate that upstream kinases (i.e., Src and Pyk2) are required but not sufficient for EGFR transactivation by TZDs. Moreover, influx of extracellular calcium through capacitative calcium entry may be an unrecognized component that provides a mechanism for the differential induction of EGFR transactivation by these compounds.