Cancer Stem Cells (CSCs) represent a small minority of cells that have properties of tumor initiation, self-renewal, unlimited proliferation, and have the ability to differentiate to give rise to progeny cells that are more differentiated and non-tumorigenic. CSCs can be derived from somatic stem cells, progenitors or even differentiated cells that have reacquired properties of self-renewal. Such populations of cells have been identified in various cancers. Here, we will focus on leukemic stem cells (LSCs) as a paradigm for CSC biology. We will discuss on the hierarchical and clonal organization of the leukemic clone, the frequency of LSCs as well as their fundamental properties and murine models used to study LSCs. Furthermore, we will describe several potential mechanisms that could be modulated to eradicate these LSCs, a therapeutic strategy which is believed to represent a major step forward in leukemia therapy.