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Next-generation whole-exome sequencing has revealed two novel genes, namely NOTCH1 and SF3B1, whose mutations predict poor outcome and preferentially associate with chemorefractory chronic lymphocytic leukemia (CLL). Analysis of 539 CLL cases documents that NOTCH1 mutations i) represent one of the most frequent cancer gene mutations involved at presentation; ii) cluster with cases harboring trisomy 12 and tend to be mutually exclusive with TP53 disruption among genetic subgroups; iii) identify high-risk patients showing poor survival similar to that associated with TP53 abnormalities; and iv) exert a prognostic role independent of widely accepted clinical and genetic risk factors. Mutations of SF3B1, a splicing factor that is a critical component of the spliceosome, recurrently associate with fludarabine-refractory CLL, occur at a low rate at CLL presentation and have a minor role in Richter transformation, corroborating the notion that CLL histological shift is molecularly distinct from chemorefractory progression without the Richter transformation.