Crizotinib is an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases (RTK) c-Met, anaplastic lymphoma kinase (ALK), and ROS1. There is convincing clinical evidence for the effectiveness in non-small-cell lung cancer (NSCLC) harboring EML4-ALK rearrangements resulting in constitutional activation of the ALK-RTK. The drug is approved for this entity, which represents no more than 3-5% of all NSCLC. However, in this population, impressive response rates are generated. The same seems to be true for ROS-1 rearrangements; however, these only occur in approximately 1% of all NSCLC. The role in c-Met altered cancers needs to be determined. Toxicities include visual impairment, nausea, peripheral edema, QT-prolongation, and liver enzyme elevation. Also, the occurrence of renal cysts is reported. Fluorescence in situ hybridization (FISH) detecting the ALK rearrangement has to be performed on tumor tissue to predict crizotinib efficacy. The role of immunohistochemistry in this setting needs to be determined. It has high concordance with FISH results when strongly positive or completely negative. The high efficacy of crizotinib in ALK- and ROS-positive lung cancer as new molecular targets beside the epidermal growth factor receptor (EGFR) underscores the importance of molecular typing in NSCLC.