The mitogen-activated protein kinase (MEK MAPK/ERK kinase) signaling pathways play a critical role in regulation of diverse cellular activities, including survival, differentiation, proliferation, motility, and angiogenesis. Therefore, MEK inhibition was recognized as a promising target for antineoplastic therapy. While multiple MEK inhibitors have been tested clinically only trametinib (GSK1120212), an oral MEK inhibitor which is selective for MEK1 and MEK2 has shown promising activity in several clinical trials on melanoma and colorectal cancer and it is being evaluated by the FDA for the treatment of metastatic melanoma. Mechanistically it was shown that trametinib induces cell cycle arrest in vitro. In this overview, important preclinical and clinical data for trametinib are presented including mechanism-based in vitro studies as well as findings from different clinical studies. Future clinical trial in different solid tumor entities will define the therapeutic role of this targeted therapy approach, possibly as a combination with other targeted therapies such as BRAF inhibitors.