The Ca2+-modulating cyclophilin ligand (CAML) protein causes stimulation of transcription factors via activation of a store-operated Ca2+ entry pathway. Since CAML is widely expressed in mammalian tissues, it may be an important regulator of Ca2+ store function. In the present study, we investigated the consequence of CAML overexpression on Ca2+ signaling using rapid confocal imaging of Fluo3-loaded NIH3T3 fibroblasts. Control and CAML-expressing cells gave concentration-dependent responses to the Ca2+ mobilizing agonist ATP. CAML expression reduced the sensitivity of the cells so that higher concentrations of ATP were needed to achieve global Ca2+ waves. The amplitudes of Ca2+ waves were significantly reduced in CAML expressing cells, consistent with earlier suggestions that CAML causes depletion of internal Ca2+ stores. With low ATP concentrations, only local Ca2+ release events were observed. CAML did not affect the characteristics of these local Ca2+ signals, suggesting that it does not directly affect Ca2+ release channels.