An overview of the MAPK signaling pathway with points of therapeutic intervention indicated. An overview of the MAPK signaling pathway with points of therapeutic intervention indicated. Activation of ERK can occur as the result of increased RTK signaling, RAS mutations, BRAF V600 and non-V600 mutation, and MEK mutations. ERK is the major effector of the pathway and leads to the phosphorylation of multiple cytoplasmic substrates. Once active, it translocates to the nucleus and activates a number of key transcription factors. To date, a number of drugs have been targeted against the MAPK pathway, including BRAF inhibitors (BRAFi), MEK inhibitors (MEKi), and now the ERK inhibitor (ERKi) ulixertinib. Inhibition of BRAF frequently leads to relief of feedback inhibition that decreases expression of negative regulators, such as a Sprouty, that facilitate recovery of MAPK pathway signaling. Inna Smalley, and Keiran S.M. Smalley Cancer Discov 2018;8:140-142 ©2018 by American Association for Cancer Research