Abstract: Provided herein, inter alia, are compositions, methods, and systems for efficient genetic manipulation of myelod cells without the use of viral vectors. Further provided are strategies for gene disruption in primary myeloid cells (e.g. of human and murine origin) using electroporation-based delivery of Cas/ribonuclear proteins (RNPs). Methods provided herein including embodiments thereof can provide near population-level genetic knockout of single and multiple targets in a range of cell types without selection or enrichment. Cellular fitness and response to immunological stimuli may be unaffected by the gene editing process.