The CBL ubiquitin ligase targets a variety of activated tyrosine kinases (TK) for degradation. Many TKs are mutationally or autocrine-activated and/or often over-expressed at the mRNA and protein levels in acute leukemias. We hypothesized that CBL is mutated in patients with acute myeloid leukemia (AML). Four of 12 patients and the MOLM-13 cell-line harbored c-CBL mutations, either RNA splicing mutations, missense mutations or a nucleotide insertion. Additionally, one of the 12 patients harbored a missense mutation in the related CBL-b gene. Each c-CBL mutation involves the structurally important alpha-helix within the linker region, while the mutation in BL-b was located in the Ub-E2 protein-binding Ring Finger. Short-interfering RNA knockdown of mutant c-CBL present in MOLM-13 cells was growth inhibitory. In summary, novel mutations in c-CBL and CBL-b have been identified in human AML and may represent potential targets for novel therapeutics.