3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a protein target that has generated considerable interest in both academia and the pharmaceutical industry. PDK1 is responsible for regulating the activity of related kinases in the AGC kinase family, including AKT, by phosphorylating a specific threonine or serine residue within the activation loop which is critical for kinase activation. Many of the kinases activated by PDK1 regulate cellular process such as cell survival, differentiation, growth, and protein expression. Although significant work has been done to understand the role of PDK1 function in cells, recently discovered potent and selective small molecule PDK1 inhibitors are providing a unique opportunity to further dissect PDK1 function and predict the pharmacological consequences of PDK1 inhibition. This Miniperspective reviews the discovery of these selective PDK1 inhibitors and highlights their value in cellular studies, the understanding of PDK1 biology, and the impact on the therapeutic potential of PDK1 inhibition in cancer.