Traditional microtubule-targeting agents, such as paclitaxel (Taxol^R) are among the most effective chemotherapeutics used for the treatment of solid tumor malignancies.  The epothilones represent a unique class of tubulin-polymerizing natural products that overcome known mechanisms of drug resistance associated with the taxanes.  Bristol-Myers Squibb is currently developing a semisynthetic epothilone analogue, ixabepilone (BMS-247550), which has provided objective responses in patients that have shown disease progression on prior chemotherapy regimens, including taxanes.  An overview of the discovery efforts leading to the identification of this novel cytotoxic macrolactam will be presented.  More recently, targeted therapies have become state-of-the-art in oncology research.  We have identified substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)-thiazole-5-carboxamides as potent multi-kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines.  SPRYCEL^R (dasatinib, BMS-354825), a 2-(aminopyrimidinyl)-derivative from this series of compounds was recently approved for adults with Philadelphia chromosome positive leukemias resistant or intolerant to prior therapy.  The structure-activity relationships, preclinical pharmacology and structural biology supporting the selection of dasatinib for clinical development will be discussed.