Acute lymphoblastic leukemia, derived from immature T or B cells, is the most common cancer in children. Current chemotherapeutic regimen are effective in over 80% of T-ALL, but the failure rate and the harshness of current treatments makes new approaches desirable. We and others have recently identified gain-of-function mutations in IL-7R alpha which serve as driver oncogenes in T cell acute lymphoblastic leukemia (T-ALL) cooperating with Ras pathway mutations. Most of the IL-7R alpha mutations contain cysteine insertions that create homodimers. These signal independently of IL-7 or the gamma-c chain of the IL-7 receptor, constitutively activating Jak1. Two approaches have been undertaken to target the IL-7R pathway in T-ALL: inhibition of Jak1, and development of monoclonal antibodies (MAbs) against IL-7R alpha. Ruxolitinib is a recently FDA approved inhibitor of Jak1, and we show it is an effective inhibitor of cells driven by mutant IL-7Ralpha in vitro and in immunodeficient mice and its effect is augmented by venetoclax, a Bcl-2 inhibitor. Two novel mouse MAbs were developed that are directed against two different epitopes on human IL-7Ralpha, and they recognize both mutant and WT proteins. MAbs were chimerized with human IgG1 to optimize antibody-dependent cell mediated cytotoxicity (ADCC). These MAbs were highly effective in ADCC assays, mediating NK cell killing of T-ALL cells harboring mutant IL-7R alpha, and in xenografts of patient T-ALL cells with mutant or WT IL-7R. These approaches are being developed as new therapeutics for acute lymphoblastic leukemia, most of which use the IL-7R pathway either through normal ligand signaling or mutations in the pathway.