Abstract: ERK1/2 is a key protein that mediates cell signal transduction, and it is involved in regulating biological processes such as chromatin remodeling, nuclear disintegration, proliferation, survival, metabolism, and cell migration and differentiation. Its overactivation is closely related to the occurrence and progression of cancer, and the mechanism is manifested as the overactivation of ERK1/2 by gene mutations of upstream pathway molecules or regulators and the reactivation of ERK1/2 after inhibition against the above targets. ERK1/2 is a potentially valuable target. In this review, the mechanism of post-translational modification and spatial regulation of ERK1/2 and the application status of corresponding small-molecule inhibitors were discussed. The current antitumor strategy of targeting and regulating ERK1/2 was summarized, and the possibility of exploring potential targets was elucidated, thus providing new insights into the developmental research of ERK1/2 as an ideal anticancer target.