Over the past 10 years, increasing evidence has accumulated that heterogeneity is a feature of hematopoietic stem cell (HSC) proliferation, self-renewal, and differentiation based on examination of these properties at a clonal level. The heterogeneous behavior of HSCs reflects the operation of a complex interplay of intrinsic and extrinsic variables. In this review, we discuss key findings from the last 5 years that reveal new insights into the mechanisms involved.