Activated Cdc42-associated kinase 1 (ACK1/TNK2) is a nonreceptor tyrosine kinase with a unique structure. It not only can act as an activated transmembrane effector of receptor tyrosine kinases (RTKs) to transmit various RTK signals but also can play a corresponding role in epigenetic regulation. A number of studies have shown that ACK1 is a carcinogenic factor. Blockage of ACK1 has been proven to be able to inhibit cancer cell survival, proliferation, migration, and radiation resistance. Thus, ACK1 is a promising potential antitumor target. To date, despite many efforts to develop ACK1 inhibitors, no specific small molecule inhibitors have entered clinical trials. This Perspective provides an overview of the structural features, biological functions, and association with diseases of ACK1 and in vitro and in vivo activities, selectivity, and therapeutic potential of small molecule ACK1 inhibitors with different chemotypes.