Treatment of chronic myelogenous leukemia (CML) has been greatly enhanced by the development of Imatinib mesylate, a specific inhibitor of the BCR/ABL tyrosine kinase. While it is clear that imatinib effectively targets BCR/ABL positive hematopoietic cells, studies examining its effect on primitive hematopoietic progenitors are much more limited. As CML arises in a primitive hematopoietic progenitor cell, it is especially important to understand the effect of imatinib on these cells. Here we review studies investigating the effect of imatinib on the proliferation and viability of primitive and committed hematopoietic progenitors in CML. We describe evidence that BCR/ABL positive progenitors may persist in patients responding to imatinib and discuss problems of resistance to imatinib. Finally we discuss studies evaluating new approaches to overcome resistance of CML progenitor cells to imatinib.