The recent discovery and application of the CRISPR-Cas9 system has enabled unprecedented versatility and simplicity in genome editing. CRISPR-Cas9-based technologies are now used to inactivate genes, correct genetic mutations, induce large genomic deletions and chromosomal translocations, and even to control transcription and epigenetics. Our lab has developed a range of modular Cas9, sgRNA, and all-in one plasmids for efficient delivery of the CRISPR-Cas9 system into murine and human hematopoietic cells. We leverage these to model translocation-driven leukemiogenesis, to delineate the sequential acquisition of mutations during leukemia progression, to perform targeted gene correction, and to control the expression of non-coding RNAs. The sgRNA constructs can be used singly or multiplexed for large-scale forward-genetic screens.