The established tumor is maintained through complex and poorly understood host-tumor interactions guiding processes such as angiogenesis. The numerous and diverse genetic alterations that accompany tumor genesis raises questions as to whether experimental cancer-promoting mutations remain relevant to tumor maintenance. Utilizing a new doxycycline-inducible H-RASV12G INK4a null mouse melanoma model, we have shown that melanoma genesis and maintenance are strictly dependent upon H-RASV12G expression. Withdrawal of doxycycline and H-RASV12G down-regulation resulted in clinical and histological regression of primary and explanted tumors. Moreover, the initial stages of regression were highlighted by dramatic activation of apoptosis in the tumor cells as well as host-derived endothelial cells. These data provide genetic evidence that H-RASV12G plays a critical role in tumor maintenance and tumor angiogenesis.