: The introduction of v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors in melanoma patients with BRAF (V600E) mutations has demonstrated significant clinical benefits. However, rarely do tumours regress completely. Frequently, the reason for this is that therapies targeting specific oncogenic mutations induce a number of intrinsic compensatory mechanisms, also known as adaptive responses or feedback loops, that enhance the pro-survival and pro-proliferative capacity of a proportion of the original tumour population, thereby resulting in tumour progression. In this review we will summarize the known adaptive responses that limit BRAF mutant therapy and discuss potential novel combinatorial therapies to overcome resistance.