Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major "unmet clinical need" in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.