CRISPR (clustered regularly interspaced short palindromic repeats), together with the Cas9 nuclease, can be used to make targeted changes to genomic DNA in mammalian cells. Now, the inventors of CRISPR-Cas9, Feng Zhang and colleagues, report the use of their method in a genome-wide knockout screen of human cells (Science 343, 84–87, 2014). They modified the method to allow for the efficient delivery of CRISPR guide RNAs and Cas9 in a single lentivirus vector. The lentiCRISPR method avoids the most common pitfall of RNA interference (RNAi) screening, incomplete RNA degradation. Using lentiCRISPR, they delivered a library of 64,751 unique guide RNAs targeting 18,080 genes to embryonic stem cells and melanoma cells and used RNA sequencing to identify guide RNAs that were depleted 14 d after transduction. The authors show that depleted RNAs correspond to essential genes. They also identified six genes expressed in melanoma cells that are involved in resistance to a chemotherapeutic agent, vemurafenib: two previously identified (NF1 and MED12) and four novel (NF2, CUL3, TADA2B and TADA1) candidates. The authors note that the method can be expanded to carry out many other types of genomic screens.