The interactions of metals with cell systems are not fully eluci-dated. Forms of metallic derivatives are highly toxic (mercury, led), and others are used in humans for diverse treatments in-cluding cancers (arsenic trioxide, cisplatin). We propose that modulation of calcium homeostasis induced by metallic deriva-tives could be an important mechanism in induced cytotoxicity. Using human cell models (neuroblastoma, osteosarcoma, cervix carcinoma, embryonic kidney cells) and confocal microscopy (Zeiss 510) with the calcium sensitive dye fluo 4-AM we found that cisplatin (cPt; 0.001 mM - 10 mM) and arsenic trioxide (As₂O₃; 0.0001 mM - 1 mM) trigger calcium signaling, the mechanism of calcium rise was drug, concentration and cell type specific. Steady state increase of [Ca²⁺]_i and calcium-spikes were observed with both substances. While the rise was partly reversible with cPt, it was not reversible with As₂O₃. As₂O₃ released calcium from the internal stores and the calcium rise was initiated by the activation of inosithol-1,4,5-triphosphate or ryanodine receptors. The cPt induced calcium rise depends on the external calcium concentration, but was modified with the IP3receptor blocker 2-APB. The modulation of [Ca²⁺]_i could be a key function to understand the beneficial as well as the toxic effects of cisplatin or As₂O₃.