Abstract Oncogene targeted therapies offer a safe and effective approach to suppress cancer since these drugs spare healthy tissues by selectively targeting driver mutations in cancer cells. Despite a strong initial response to these therapies, however, patients eventually progress and relapse within months of treatment due to the survival of residual tumor cells. These residual disease cells are crucial to eradicate since these cells often serve as the reservoir for resistance and relapse. However, the biological and immunological properties of residual tumor cells are poorly understood. We studied the immunological properties of residual cancer cells and the molecular mechanisms governing it. Using a BRAF mutant mouse melanoma model, we found that residual cancer cells that survive in vitro BRAF therapy exhibit immune evasion in vivo. Our preliminary data suggest residual tumor cells evade the immune system by targeting macrophages of the immune system through upregulation of “don’t eat me” markers such as CD47 (cluster of differentiation 47). Our findings are reproducible in human BRAF, ALK and KRAS mutant cancer cell lines that all show CD47 upregulation upon treatment of respective targeted therapies. Importantly, CD47 blockade has been shown to have an antitumor effect in many mouse tumor models and is currently under investigation in clinical trials to determine its efficacy in human patients. Thus, our preliminary data linking oncogene targeted therapies to CD47 upregulation has significant implications for combining these therapies in clinical practice. To further investigate our findings, we propose a series of integrative transcriptomics and functional genomics approaches to uncover potential mechanisms to target and engineer the immune-mediated clearance of residual tumor cells.