Cell proliferation, survival, differentiation, migration and metabolism are some of the fundamental cellular processes tightly controlled by the activity of tyrosine-kinase receptors (RTKs). The aberrant signaling of RTKs contributes to cancer growth and survival and has become important target for therapeutic approaches. Well-characterized kinase molecular target in lung cancer, in particular in non-small cell lung cancer (NSCLC), is the activated epidermal growth factor receptor (EGFR) pathway. More recently, the oncogenic role of other two tyrosine-kinases, the hepatocyte growth factor receptor (MET) and the anaplastic lymphoma kinase (ALK), has been recognized. Many different therapeutic strategies have been investigated with the goal to inhibit these receptors, subsequent downstream signaling cascades and arrest tumor growth. This review will discuss the MET and ALK pathways, the different strategies of their inhibition and the potential approaches to overcome acquired resistance to kinase inhibitors in these two genes.