While it remains to be determined how universal the pleiotropy of the Rac1-driven drug resistance mechanism is in BRAF V600-mutant melanoma, these data indicate that Rac1 signaling has the potential to drive MAPKi resistance via multiple mechanisms that include the YAP/TAZ, Jun kinase, and p38 MAPK pathways. The gene discussed is MAPK9; the disease is melanoma.