Abstract: Metalloenzyme is a generic term normally used for the enzymes containing functionally and/or structurally essential metal ions, which are widely involved in key physiological and pathological processes, and are a colony of important drug targets. Electronic and geometric structures of metal-binding sites usually have complicated, flexible, dynamic features, which make computer-aided drug design more challenging. This paper summarizes the research progress, strengths and challenges for metal-binding pharmacophores, structure-based drug design, and artificial intelligence used in metalloenzyme-targeted drug discovery, with the hope to provide reference and reflection for high-efficient innovative drug discovery targeting metalloenzymes.