Hyperlipidemia is an important risk factor for coronary heart disease. Chadwick and colleagues report significantly reduced blood lipid levels following CRISPR-based in vivo genome editing in mice to introduce loss-of-function mutations in ANGPTL3, a lipoprotein lipase inhibitor. The treatments were effective in both healthy and Lplr−/− mice and comparable to PCSK9-targeted genome editing, without causing off-target mutations.