Protein and lipid kinases are known to play key roles in maintaining cellular health. Disruption in kinase signaling cascades can lead to a host of diseases and conditions, including diabetes, cancer, Alzheimer’s disease, and bipolar disorder. A subset of kinases requires an activating phosphorylation within a region of their catalytic domains known as the activation loop to achieve maximum enzymatic activity. While this can be mediated via an upstream kinase, often it is the result of an autophosphorylation event, which sets up the paradoxical question of how the first kinase becomes phosphorylated. Recently, mechanisms for this first autophosphorylation have been elucidated for a handful of kinases and they broadly fall into two categories: cis-autophosphorylation, where a.......