Hematopoietic stem cells (HSCs) possess the ability to self-renew and to differentiate to mature progeny along multiple different hematopoietic lineages. The function of HSCs depends upon the signals from surrounding cells found within the highly specialized microenvironment termed the hematopoietic stem cell niche. Understanding and exploiting the HSC niche is a goal of basic scientists and clinicians alike. Recent studies have focused on defining the cellular components and molecular factors critical to this microenvironment. Here we review recent findings, discuss unresolved questions, and examine the clinical implications of our current knowledge of the HSC niche.