Genetic editing of hematopoietic stem and progenitor cells can be employed to understand gene-function relationships underlying hematopoietic cell biology, leading to new therapeutic approaches to treat disease. The ability to collect, purify, and manipulate primary cells outside the body permits testing of many different gene editing approaches. RNA-guided nucleases, such as CRISPR, have revolutionized gene editing based simply on Watson-Crick base-pairing, employed to direct activity to specific genomic loci. Given the ease and affordability of synthetic, custom RNA guides, testing of precision edits or large random pools in high-throughput screening studies is now widely available. With the ever-growing number of CRISPR nucleases being discovered or engineered, researchers now have a plethora of options for directed genomic change, including single base edits, nicks or double-stranded DNA cuts with blunt or staggered ends, as well as the ability to target CRISPR to other cellular oligonucleotides such as RNA or mitochondrial DNA. Except for single base editing strategies, precise rewriting of larger segments of the genetic code requires delivery of an additional component, templated DNA oligonucleotide(s) encoding the desired changes flanked by homologous sequences that permit recombination at or near the site of CRISPR activity. Altogether, the ever-growing CRISPR gene editing toolkit is an invaluable resource. This chapter outlines available technologies and the strategies for applying CRISPR-based editing in hematopoietic stem and progenitor cells.