Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.