BRAF-mutant metastatic colorectal cancer comprises a biologically distinct and clinically aggressive subset of metastatic colorectal cancer. Early attempts to apply single-agent BRAF inhibition failed because of rapid acquired resistance and reactivation of mitogen-activated protein kinase signaling. Over the last decade, rational combinations (BRAF inhibitors and epidermal growth factor receptor inhibitors with or without mitogen-activated protein kinase kinase inhibitors) have become the standard of care in the refractory setting and are now being evaluated upfront, whereas a wave of next-generation approaches (extracellular signal-regulated kinase and SHP2 inhibitors, receptor tyrosine kinase-targeted agents, and immunotherapy combinations) aims to prevent or overcome resistance. The objective of this comprehensive review was to summarize historic therapeutic approaches, current standards, and the mechanistic rationale and clinical development of next-generation strategies to combat resistance in BRAF-mutant metastatic colorectal cancer.