Leucine-zipper and sterile-α motif kinase (ZAK) is a member of mixed-lineage kinase family (MLKs), which is considered as a new potential target for different physiological disorders, including myocardial hypertrophy and cardiac fibrosis, inflammation and cancer. However, the progress on its biological functions and small molecule inhibitors is limited. Only several multi-kinases inhibitors are reported to non-selectively bind with ZAK with various potencies. Herein, we provide an updated overview on the biological functions and small molecular inhibitors of ZAKs.