Recent genomic analyses of childhood and adult B-precursor acute lymphoblastic leukemia (ALL) samples have identified novel genetic alterations in essential lymphoid development and signal transduction pathways, providing insight into the pathogenesis of high risk ALL associated with treatment failure. Particular advances have been made in unraveling the genetics of ALL associated with overexpression of the cytokine receptor-like factor 2 gene (CRLF2), which is frequently accompanied by simultaneous activating mutations in genes encoding Ikaros (IKZF1), Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), and/or the IL-7 receptor alpha chain (IL7RA). Children and adults with high risk CRLF2-overexpressing ALL have high rates of relapse and dismal overall survival. Various groups have thus attempted to characterize the biochemical consequences of these genetic lesions via preclinical models with the goal of identifying targets for new therapies. These studies provide early data suggesting the promise of signal transduction inhibitors (STIs) of the JAK/STAT and PI3K pathways for CRLF2-overexpressing ALL. Additional research efforts continue to elucidate these aberrant signaling networks to provide rationale for bringing STIs into the clinic for these high risk patients. This review highlights the current knowledge of the incidence, prognostic significance, and biology of CRLF2-overexpressing ALL and the future directions for development of targeted therapies.