Aldehyde oxidase (AO,a EC 1.2.3.1) has for many years been recognized as a metabolizing enzyme contained within the cytosolic compartment of many tissues and in many species. The first literature reference to AO dates from the 1930s, but literature citations to this enzyme have been steadily growing ever since, especially in the past decade. It has been increasingly recognized in this past decade that AO, through its unique structure, distribution, and substrate recognition, has an important role to play in the metabolism of drugs. In this timely Perspective, we present the current knowledge of the enzyme's expression, its structure, and its distribution across species. We offer an analysis of substrates recognized by AO and highlight clinical examples where metabolism by this enzyme has had significant clinical impact or led to the termination of a drug development program. Finally, through analysis of the structure of known substrates, we present data to suggest the significant impact AO could play on future drug discovery programs along with strategies that could be employed to mitigate this.