Purpose of review: Although immune checkpoint inhibitors and small molecule inhibitors targeting the MAPK pathway have revolutionized the management of metastatic melanoma, long-term disease control occurs only for a minority of patients because of multiple resistance mechanisms. One way to tackle resistance is to develop the next-generation of RAF, MEK and ERK inhibitors using our understanding of the molecular mechanisms that fine-tune the MAPK pathway. Recent findings: Studies on the regulation of the MAPK pathway have revealed a dominant role for homo-dimerization and hetero-dimerization of RAF, MEK and ERK. Allosteric inhibitors that break these dimers are, therefore, undergoing various stages of preclinical and clinical evaluation. Novel MEK inhibitors are less susceptible to differences in MEK's activation state and do not drive the compensatory activation of MEK that could limit efficacy. Innovations in targeting ERK originate from dual inhibitors that block MEK-catalyzed ERK phosphorylation, thereby limiting the extent of ERK reactivation following feedback relief. Summary: The primary goal in RAF, MEK and ERK inhibitors' development is to produce molecules with less inhibitor paradox and off-target effects, giving robust and sustained MAPK pathway inhibition.