The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is one of the best-characterized kinase cascades in cancer cell biology. It is triggered by either growth factors or activating mutations of major oncogenic proteins in this pathway, the most common being Ras and Raf. Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers. Targeting these kinases offers promise of novel therapies. MEK inhibitors (MEKi) are currently under evaluation in clinical trials and many have shown activity. In this review, we comprehensively examine the role of the MEK pathway in carcinogenesis and its therapeutic potential in cancer patients, with a focus on MEKi. We describe the clinical perspectives of MEKi in the two main models of Ras-ERK driven tumors, BRAF-mutant ("addicted" to the pathway) and KRAS-mutant (non-"addicted"). We also highlight the known mechanisms of resistance to MEKi and emerging strategies to overcome it.