The hepatocyte growth factor (HGF)-mesenchymal-epithelial transition factor (MET) pathway has a key role in carcinogenesis; it is implicated in proliferation, inhibition of apoptosis, angiogenesis, migration, invasiveness, and metastasis. All of these molecular events are driven through membrane and intracellular coplayers and several downstream effector proteins. MET has been shown to cross react with epithelial growth factor receptor (EGFR) proteins and possibly substitutes their activity, thus conferring resistance to EGFR-targeting drugs. Therefore, identification of MET inhibitors might lead to new treatments for MET-triggered neoplasia and improve the sensitivity of molecularly targeted antineoplastic compounds that are currently in use. In this Review, we outline current data regarding the HGF-MET pathway during carcinogenesis and the strategies for therapeutic targeting of this pathway. We also discuss the rationale and future perspectives of the combinatorial blockade of HGF-MET and EGFR signalling cascades in cancer treatment.