A significant portion of recent drug development efforts has been focused on protein kinases. More than a hundred different compounds are currently under clinical trials and nearly 30% of all the scientific articles in drug discovery are on protein kinase inhibitors. Protein kinases are very flexible targets and undergo significant conformational changes upon activation and during the catalytic cycle. This flexibility can be exploited in drug discovery. Some of the inactive states that emerge during the conformational changes are targeted by various inhibitors with a significant gain in selectivity. Here, we review the recent advances being made in understanding the details and the mechanism of these conformational changes thanks to the progress in molecular dynamics and free energy algorithms as well as to the availability of specialized computer hardware.