Cadmium is a toxic metal that initiates both mitogenic responses and cell death. We show that Cd²⁺ increases phosphorylation and activity of Ca²⁺/calmodulin-dependent protein kinase II (CaMK-II) in mesangial cells, in a concentration-dependent manner. Activation is biphasic with peaks at 1–5min and 4–6h. Cadmium also activates Erk, but this appears to be independent of CaMK-II. At 10–20μM, Cd²⁺ initiates apoptosis in 25–55% of mesangial cells by 6h. Inhibition of CaMK-II, but not of Erk, suppresses Cd²⁺-induced apoptosis. We conclude that activation of CaMK-II by Cd²⁺ contributes to apoptotic cell death, independent of Erk activation.