Numerous epidemiological studies and recent meta-analyses, described in Chapter 6, support the association of formaldehyde exposure with leukemia. In this chapter, we first introduce general leukemogenesis and all types of leukemias and then discuss the leukemic stem cell theory, which is generally accepted in the scientific community. Examples of chemically induced leukemias, such as those caused by formaldehyde or benzene, are evaluated in relation to the leukemic stem cell theory. Next, the biological plausibility of the association and potential mechanisms of formaldehyde-induced leukemia are discussed. Specifically, four models are hypothesized and presented: (1) targeting bone marrow stem cells directly; (2) targeting stem cells in the circulating blood; (3) targeting stem cells in the oral/nasal tissues; and most recently, (4) targeting stem cells in the lungs. Finally, the biological plausibility of formaldehyde-induced hematopoietic stem cell toxicity in bone marrow, blood, and, pulmonary and nasal tissues to initiate leukemia stem cells is discussed in detail.