The pharmaceutical industry has traditionally targeted the inhibition of dysregulated kinases to treat diseases such as cancer and inflammatory disorders. In contrast to the human genome sequencing project, which aimed to identify novel biological targets, the possibility of activating kinases uses known targets in a novel manner. In an approach that is similar to other target classes (eg, GPCRs and nuclear receptors), transient upregulation of kinase function using small molecules has been increasingly demonstrated to lead to favorable disease outcomes. This review discusses direct small-molecule kinase activators: specifically, how these molecules were discovered, characterized, evaluated and developed into drug leads. The choice of potential targets, the mechanisms of activation and the common strategies used to discover activators are also highlighted.