Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein, Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor protein is yet to be determined. In this study, we present several lines of evidence from cancer databases, immunoblotting of cancer cells, proliferation and xenograft assays as well as DNA microarray analysis to demonstrate the role of MOAP-1 as a tumor suppressor protein. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to mRNA downregulation and the rapid proteasomal degradation of MOAP-1 that could be reversed utilizing the proteasome inhibitor, MG132. Overexpression of MOAP-1 in several cancer cell lines resulted in reduced tumorigenesis and upregulation of genes involved in cancer regulatory pathways that includes apoptosis (p53, Fas and MST1), DNA damage control (PARP and ATM), those within the cell metabolism (IR-alpha, IR-beta and AMPK) and a stablizing effect on microtubules. The loss of RASSF1A (an upstream regulator of MOAP-1) is one of the earliest detectable epigenetically silenced tumor suppressor proteins in cancer and we speculate that the additional loss of function of MOAP-1 may be a second hit to functionally compromise the RASSF1A/MOAP-1 death receptor dependent pathway and drive tumorigenesi