Melanoma, the third most common skin cancer, is characterized by its heterogeneity and propensity to metastasize. The tumor is composed of genetically divergent subpopulations, including cancer stem-like cells (CSCs) and non-CSCs. CSCs, characterized by unique surface proteins and aberrant signaling pathways, promote melanoma progression, drug resistance, and recurrence. Common genetic alterations in functional genes such as BRAF, NRAS, TP53, and NF1 contribute to melanoma development, with BRAFV600E mutations being the most prevalent. While BRAFV600E targeting improves overall survival, long-term efficacy is limited due to acquired resistance. Melanoma heterogeneity, driven by genetic and epigenetic changes, results in intratumoral and intertumoral heterogeneity. CSCs, identified by markers like CD271 and CD133, exhibit plasticity and resistance to chemotherapy and radiation therapy. Treatment resistance mechanisms include compensatory signaling pathways, such as ARAF and CRAF activation, and the re-activation of RTKs. Immune checkpoint inhibitors and adoptive cell therapy have shown promise in melanoma treatment. However, CSCs' ability to evade immune responses and maintain drug resistance remains a significant challenge. Understanding these mechanisms may lead to more effective therapeutic strategies.Melanoma, the third most common skin cancer, is characterized by its heterogeneity and propensity to metastasize. The tumor is composed of genetically divergent subpopulations, including cancer stem-like cells (CSCs) and non-CSCs. CSCs, characterized by unique surface proteins and aberrant signaling pathways, promote melanoma progression, drug resistance, and recurrence. Common genetic alterations in functional genes such as BRAF, NRAS, TP53, and NF1 contribute to melanoma development, with BRAFV600E mutations being the most prevalent. While BRAFV600E targeting improves overall survival, long-term efficacy is limited due to acquired resistance. Melanoma heterogeneity, driven by genetic and epigenetic changes, results in intratumoral and intertumoral heterogeneity. CSCs, identified by markers like CD271 and CD133, exhibit plasticity and resistance to chemotherapy and radiation therapy. Treatment resistance mechanisms include compensatory signaling pathways, such as ARAF and CRAF activation, and the re-activation of RTKs. Immune checkpoint inhibitors and adoptive cell therapy have shown promise in melanoma treatment. However, CSCs' ability to evade immune responses and maintain drug resistance remains a significant challenge. Understanding these mechanisms may lead to more effective therapeutic strategies.