We have recently identified substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides as potent multi- kinase inhibitors with excellent antiproliferative activity against solid tumor and hematological cell lines. Moreover, the orally bioavailable, 2-aminopyrimidinyl derivative dasatinib (SPRYCEL®) retains activity in several clinically relevant imatinib-resistant cell lines and provides complete tumor regressions at multiple dose levels in wild-type and imatinib-resistant in vivo tumor models of chronic myelogenous leukemia (CML). Consistent with these preclinical findings, dasatinib demonstrated significant hematologic and cytogenetic response rates in CML and Ph+ ALL patients with resistance or intolerance to imatinib. Crystallographic analysis of dasatinib bound to the Abl kinase domain reveals that dasatinib binds to the activated form of the kinase. The crystal structure also provides a mechanistic rationale for the ability of dasatinib to overcome all known imatinib-resistant Bcr-Abl mutants, except for the T315I variant. The structure-activity relationship studies, preclinical pharmacology, and structural biology supporting the selection of dasatinib for clinical development will be discussed.