Cancer relapse due to outgrowth of minimal residual disease (MRD) cells is a major contributor to cancer mortality. Conversely, generating effective methods to induce death in MRD cancer cells could enable a transformative shift in patient survival and longevity 1–3. By definition, MRD cells contrast to most cancer cells in that they can evade immunological detection and circumvent elimination by pharmacological treatments. It is unknown whether cells destined to become MRD cells can be produced during tumor initiation and at early stages of tumorigenesis. Furthermore, it unclear if extensive cancer cell heterogeneity and diversification is a necessary requirement for cancer cells to gain the ability to become MRD. Our overall objective is to determine if mutant melanocyte stem cells (McSCs), acting as melanoma cells of origin, generate immediate descendants that will ultimately become MRD. Specifically, we hypothesize that following melanoma initiation, melanoma origin cells establish MRD capability in a select sub-population of progeny by continuing intrinsic immune privilege and relative cell cycle quiescence.