Although kinases of the PIM family have been suggested as targets for the development of drugs with anticancer activity, selective inhibitors that would validate PIM as a target for clinical intervention have not yet been identified. Here, Pogacic and colleagues have identified imidazo[1,2-b]pyridazines as selective and potent inhibitors of PIM1 and PIM3 kinases, using in vitro binding as well as enzyme kinetic assays. Analysis of the high-resolution crystal structure of a complex with one of the lead compounds revealed that these inhibitors form no classical hydrogen bonds with the kinase hinge region. Formation of hydrogen bonds to the hinge backbone is a hallmark for the binding of ATP and ATP mimetic inhibitors to the kinase active site, rendering imidazo[1,2-b]pyridazines as ATP competitive but not ATP mimetic PIM inhibitors. This binding mode and screening of a focused library resulted in the identification of selective PIM inhibitors that showed only weak cross-reactivity with one other kinase in a panel of 50 serine/threonine kinases screened. The authors show that imidazo[1,2-b]pyridazines also inhibit PIM in cells and have in vitro antileukemic activity using primary cells from acute myelogenous leukemia patients. For details, see the article by Pogacic and colleagues on page 6916 of this issue.