The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma). We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years. MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds.