This chapter focuses on how interactions between genes and environment impact the origin, progression, and response to therapy of hematopoietic tumors. Six essential, acquired characteristics are necessary for cellular transformation. These characteristics are: the ability to sustain proliferative signaling; the evasion of growth suppression; the ability to resist cell death; the capacity to enable reproductive immortality; the ability to induce angiogenesis; and the capacity to invade tissues and metastasize. Various models have been proposed to explain how cells acquire the features that lead to neoplastic transformation and eventually to clinical cancer. One model describes the process as stepwise accumulation of mutations that reduce constraints on growth and eventually promote transformation. Although this model is overly simplistic and technically flawed, it is nevertheless useful to convey the events that lead to carcinogenesis.