Significance Many drugs trigger changes to the structure of their target receptor upon binding. These conformational effects are thought to be an essential part of molecular recognition but have proven challenging to quantify. Using a high-throughput method for tracking structural changes in a protein kinase in solution, we discovered that many clinically important cancer drugs trigger substantial structural changes to their target protein kinase Aurora A, and that these effects systematically account for the ability of the drugs to differentiate between different biochemical forms of Aurora A. The results provide insight into mechanisms of drug selectivity and suggest strategies for tailoring inhibitors to target certain cancers in which Aurora A has been dysregulated in different ways.