Summary: The most commonly used therapies in the treatment of melanoma are targeted therapies with BRAF and MEK inhibitors (BRAFi/MEKi) and monoclonal antibodies targeting immune checkpoint inhibitors such as cytotoxic T cell antigen 4 (CTLA4) and programmed cell death 1 (PD-1). Components of the tumor microenvironment - regulatory T lymphocytes (Treg), tumor-associated macrophages (TAMs), myeloid suppressor cells (MDSC) and cancer-associated fibroblasts (CAFs) are involved in the mechanisms of drug resistance to the treatment of melanoma cells. Interleukin 10 (IL-10)-mediated Tregs inhibit recruitment of CD8 + T cells, resulting in tumor immunotolerance. TAMs, MDSC and CAFs secrete vascular endothelial growth factor (VEGF), which causes neovascularization and contributes to tumor progression. In addition, CAFs secrete also a fibroblast activation protein (FAB), which inhibits the activity and recruitment of T lymphocytes within the tumor. BRAFi can induce autophagy by increasing endoplasmic reticulum stress, which promotes treatment resistance. Activation of certain signaling pathways in melanoma cells may promote epithelial-mesenchymal transition (EMT), which causes tumor invasion. Drug resistance is also induced by melanoma stem cells. Overexpression of transcription factors such as YAP1 (Yes1 Associated Transcriptional Regulator), TAZ (Tafazzin, Phospholipid-Lysophospholipid Transacylase) and TEAD (TEA Domain Transcription Factor 1) by melanoma stem cells increases the survival of these cells and tumor progression. New strategies to overcome resistance to therapy are at the preclinical stage.