Most small-molecule kinase inhibitors interact with multiple members of the protein kinase family; achieving selective inhibition of specific protein kinases is challenging. These two papers describe studies of kinase inhibitor selectivity. Anastassiadis et al. profiled the activity of 178 kinase inhibitors against a panel of 300 protein kinases. They identified kinases that were inhibited by many compounds, as well as kinases that were resistant to small-molecule inhibition, and showed that many off-target interactions occur with seemingly unrelated kinases. They also identified potential lead compounds for orphan kinases and for the development of multitargeted kinase inhibitors. Davis et al. tested the interaction of 72 kinase inhibitors with 442 kinases. They showed that, as a group, type II inhibitors — which bind adjacently to the ATP site and prefer an inactive kinase conformation — were generally more selective than type I inhibitors but several individual type I inhibitors were among the most selective identified. Furthermore, they identified a class of inhibitors that was broadly active against a single subfamily of kinases but selective outside that subfamily, and several compounds that were active against orphan kinases. Together, these papers provide information that could aid the identification of selective kinase inhibitors for use as tool compounds, and assist in kinase inhibitor drug discovery.