Metal-based drugs and imaging agents are extensively used in the clinic for the treatment and diagnosis of cancers and a wide range of other diseases. The current clinical arsenal of compounds operate via a limited number of mechanisms, whereas new putative compounds explore alternative mechanisms of action, which could potentially bring new chemotherapeutic approaches into the clinic. In this review, metal-based drugs and imaging agents are characterized according to their primary mode of action, and the key properties and features of each class of compounds are defined wherever possible. A better understanding of the roles played by metal compounds at a mechanistic level will help to deliver new metal-based therapies to the clinic by providing an alternative, targeted, and rational approach to supplement non-targeted screening of novel chemical entities for biological activity.