The incidence of melanoma is increasing globally, even in the wake of increased risk factor awareness and a growing body of advanced therapeutic options. It is apparent that the treatment of melanoma will remain a topic of worry in areas of the world under high ultraviolet exposure and areas that harbor individuals with fair skin phenotypes. In the wake of such concern, the potential of immunotherapy and various targeted therapeutics to treat late-stage melanoma is increasing. In addition to the growing arsenal of PD-1 and PD-L1 immune checkpoint inhibitors, other targeted therapies are being developed and tested to treat melanoma. BRAF/MEK inhibitors target a key proliferative pathway in melanoma, offering clinical benefit but limited durability. Next-generation agents and triplet therapy with immunotherapy aim to improve outcomes. Androgen receptor signaling may also modulate responses to both targeted and immune-based treatments. Bispecific T cell engagers assist with guiding the body’s own T cells to tumors where they release toxins that kill the tumor cell. Personalized neoantigen vaccines target tumor-specific antigens by sequencing a patient’s cancerous cells to create tailored vaccines that elicit a strong and specific immune response. Tumor-infiltrating lymphocytes are autologous lymphocytes reinfused back into the host that are showing efficacy in the treatment of advanced melanoma. Together, these therapies are advancing the arsenal of chemotherapeutic options that can be used to inhibit the progression of melanoma.