Development of targeted therapies has significantly improved the prognosis of patients with melanoma. Nevertheless, drug resistance is one of the most common complications that occurs within a few months after beginning targeted therapy and is responsible for tumor recurrence at an advanced cancer stage. Tumors comprise a complex microenvironment that consists of resident and recruited cells. Specifically, macrophages are one of the most abundant non-tumor cell types within melanomas and high infiltration of macrophages is associated with poor prognosis. These characteristics suggest that macrophages in melanoma could enable resistance to cytotoxic therapies.The purpose of the first study was to investigate the role of macrophages in driving heterogenous treatment responses and reprogramming cancer cells by concurrent tracking of tumor cells and macrophages under targeted therapy pressure over an extended period. This study utilized clinically relevant in vivo Braf-mutant melanoma models and reporter mice to assess the dynamic evolution of the macrophage population at three different time points generated by therapy pressure-induced stress: untreated-growing melanomas; regressed-persistent tumors following 3 weeks of treatment; and resistant-rebound melanomas. Results from this study determined that Ccr2+ monocyte derived macrophages infiltrate during a drug-tolerant persistent state, prior to the development of acquired resistance, promoting a stable drug resistance phenotype in rebounding tumors. The purpose of the second study was to characterize the dermal macrophages in melanoma tissue that differ from non-tumorous dorsal skin. This study utilized fate-mapping strategies, EdU incorporation assays and DTR-mediated ablation methods to examine the role of the Cx3cr1+ macrophage subset. The results of this study indicated the presence of self-proliferating macrophages in tumor circumstances, with Cx3cr1+ macrophages demonstrating anti-tumoral capacity. This thesis provides valuable insights into the dynamic roles of macrophages in melanoma and the importance of understanding tumor specific microenvironment, which may ultimately pave the way for novel therapeutic strategies.