The Raf-MEK-ERK signaling pathway promotes cell cycle progression and cell proliferation, and it has been shown to play a key role in tumorigenesis and cancer cell survival. Targeting MEK to inhibit the activity of this survival pathway has been a logical strategy for treating cancers. Several MEK inhibitors have been developed and widely used in laboratories as tools to study the signaling pathway. Despite their promising anti-tumor activity in preclinical studies, MEK inhibitors have failed to generate satisfactory responses in clinical trials. Here we review the history of two catego-ries of highly selective MEK inhibitors: non–ATP-competitive small-molecule inhibitors (PD 098059, U0126, PD 184352 and its derivatives) and biological inhibitors (anthrax lethal toxin and Yersinia outer protein J). This review presents a dis-cussion of the mechanisms of these inhibitors and is intended to provide insights into the potential applications of these inhibitors to cancer studies and treatments. Keywords: Allosteric inhibition, anthrax lethal toxin (LeTx), ARRY-142886 (AZD6244), MAPK/ERK kinase (MEK), mito-gen-activated protein kinase (MAPK), mitogen-activated protein kinase kinase (MKK), PD 184352 (CI-1040), Yersinia outer protein J (YopJ).