The Bcl-2/Bcl-xL/Bax and the Ras/Raf/MEK/ERK (MAPK) pathways are often deregulated in many human cancers and especially in acute lymphoblastic leukemia and acute myeloid leukemia. A result of molecular alterations of these pathways is uncontrolled cell growth and survival, ultimately resulting in oncogenic transformation and progression. Aberrant expression of Bcl-2/Bax and MAPK can lead to therapeutic resistance. In this review, the Bcl-2 and MAPK pathways are analyzed, focusing the attention on their molecular alterations, and the complex interactions between these signaling cascades are also analyzed. The observation that both MAPK and Bcl-2/Bax signaling play a central role in the pathogenesis of human cancer suggests that this kinase cascade represents a novel opportunity for the development of new anticancer targeted therapies designed to be less toxic than conventional chemotherapy. The evidence that they are often implicated in sensitivity and resistance to leukemia therapy suggests that characterization of the cancer genome may offer personalized cancer genomic information that can lead to the formulation of much more effective personalized therapy.