CDK9 Cyclin-dependent kinase 9 (CDK9) and cyclin T or cyclin K constitute positive transcription elongation factor b (P-TEFb), a well-validated target for the treatment of several diseases including cancer. Several cancer drug candidates have been clinically evaluated as CDK9 inhibitors. Unfortunately, these molecules lack selectivity for CDK9, leading to major off-target effects and hampering their potential clinical use. Therefore, there is a pressing demand to discover highly selective inhibitors of CDK9. We recently designed and synthesized a few prototype molecules that selectively inhibit CDK9 among several CDKs (J. Med. Chem. 2013, 56, 640-59), and rationalized their selectivity over CDK2 (J. Med. Chem. 2013, 56 , 660-70). We are currently adapting the scaffold of these molecules to achieve even higher selectivity over a wider range of kinases. We also combined available crystallographic data of CDK2/9 with in silico modeling in a novel approach, to design potential allosteric inhibitors to target a little-known allosteric binding site of CDK9, by exploiting structural dissimilarities between kinases in outside the traditionally targeted ATP-binding pocket. We anticipate that our highly selective CDK9 inhibitors will provide effective cancer treatments with minimal side effects.