Death associated protein kinase (DAP-kinase) is a pro-apoptotic calcium/calmodulin-regulated serine/threonine kinase with a multidomain structure that participates in a wide array of apoptotic systems initiated by IFN-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. At various stages during tumor development, cells are subjected to apoptosis inducing stimuli and genetic mutations causing inhibition of apoptosis confer a selective advantage to cells. Thus, apoptosis and its regulation play an important role in tumor initiation, progression and metastasis. It has been demonstrated that the tumor-suppressive properties of DAP-kinase operate at two different apoptotic checkpoints in the course of tumor development; first, during the early oncogene-activated apoptotic checkpoint mediated by p19ARF-p53 pathway and second, during the late stages of metastasizing cells entering the circulation after detachment from extracellular matrix. Promoter hypermethylation of DAP-kinase has been observed in a high variety of primary tumors including head and neck tumors, and non-small cell lung cancers, where an association with poor prognosis was also noted. Notably, high frequencies of DAP-kinase methylation have been found in B cell lymphomas and myeloma, where loss of control of c-Myc induced hyperproliferation from inactivated DAP-kinase may possibly play an important role in the pathogenesis of these B cell neoplasms.