The CRISPR–Cas system is a defence mechanism that uses guide RNAs (gRNAs) and Cas nucleases to bind to complementary sequences in invading DNA and degrade them. Liao et al. transfected human cell lines with Cas9 and with gRNAs targeting the long terminal repeats (LTRs) of HIV-1, which led to reduced infection of these cells by HIV-1, compared with wild-type cells. Similarly, CRISPR–Cas9 transfection into cell lines with integrated virus reduced the levels of proviral DNA. Furthermore, human T cell lines engineered to stably express Cas9 and LTR-specific gRNAs maintained a low level of viral infection even 14 days post-infection with HIV-1. Finally, the authors showed that CRISPR–Cas9 efficiently reduced virus production in primary human cells, demonstrating that expression of the CRISPR–Cas9 system in humans confers protection against HIV-1 infection.