In non‐small cell lung cancer (NSCLC), the anaplastic lymphoma kinase (ALK) fusion protein is a result of a chromosomal inversion, which commonly results in a fusion with echinoderm microtubule‐associated protein‐like 4 (EML4). Crizotinib has demonstrated impressive efficacy in several ALK‐driven and c‐Met‐driven xenograft tumor models. It is a multitargeted RTK inhibitor for c‐Met, ALK, and ROS1 kinases. Crizotinib was identified using structure‐based drug design techniques and the medicinal chemistry principle to simultaneously optimize the compound's binding effectiveness and the associated absorption, distribution, metabolism, and excretion (ADME) properties. The chapter also provides an overview of the synthesis of crizotinib from a chronological perspective and, summarizes the descriptions of the various breakthroughs in the chemistry as they impacted the production of the API.