Calpains are a family of cysteine proteases existing primarily in two forms designated by the $Ca^{2+}$ concentration needed for activation in vitro, $mu$-calpain (calpain-I) and m-calpain (calpain-II). The physiologica1 roles of calpains remain unclear. Many groups have proposed a role for calpains In apoptosis, but their patterns of activation are not well characterized. Calpains have been implicated in neutrophil apoptosis, glucocorticoid-induced thymocyte apoptosis, as well as many other apoptotic pathways. Calpain activation in apoptosis is usually linked upstream or downstream to caspase activation, or in a parallel pathway alongside caspase activation. Calpains have been suggested to be involved in DNA fragmentation (via endonuclease activation), but also as effector proteases that cleave cellular proteins involved in DNA repair, membrane associated proteins and other homeostatic regulatory proteins. Recently, our laboratory demonstrated $mu$-calpain activation in NAD(P)H: quinone oxidoreducatse 1 (NQO1)-expressing cells after exposure to $eta$-lapachone, a novel quinone and potential chemo- and radio-therapeutic agent. Increased cytosolic $Ca^{2+}$ in NQO1-expressing cells after $eta$-lapachone exposures were shown to lead to $mu$-calpain activation. In turn, $mu$-calpain activation was important for substrate proteolysis and DNA fragmentation associated with apoptosis. Upon activation, $mu$-calpain translocated to the nucleus where it could proteolytically cleave PARP and p53. We provided evidence that $eta$-lapachone-induced, $mu$-calpain stimulated, apoptosis did not involve any of the known caspases; known apoptotic caspases were not activated after $eta$-lapachone treatment of NQO1-expressing cells, nor did caspase inhibitors have any effect on $eta$-1apachone-induced cell death. Elucidation of processes by which $eta$-1apachone-stimulated $mu$-calpain activation and calpains ability to activate endonucleases and induce apoptosis independent of caspase activity will be needed to further develop/modulate $eta$-lapachone for treatment of human cancers that over-express NQO1.