Kinase proteins are key to signaling in eukaryotic cells, so it is not surprising that their dysfunction has been implicated in human diseases such as cancer and inflammatory disorders. As a result, kinases have become important targets for drug discovery. The majority of kinase inhibitors bind to the ATP-binding site, which is highly conserved among the different kinases. In order to increase inhibitor selectivity toward a desired target kinase, the focus has turned to developing inhibitors which bind to inactive conformations or allosteric sites.The techniques frequently used to study inhibitor binding such as X-ray crystallography and docking are limited because they only sample a single structure. In reality, a protein is characterized by an ensemble of structures. Free energy calculations can sample many different conformations and provide a clear picture of the mechanisms of inhibitor binding. Since straightforward molecular dynamics simulations suffer from a time scale problem we use a novel computational technique, metadynamics, to enhance sampling. Using metadynamics calculations we propose to investigate the binding mechanisms of inhibitors which target the inactive conformation and allosteric sites.We focus on two proteins which are targets for cancer therapy: p38 mitogen-activated protein kinase and Abl.