The advent of biologic therapy has enhanced our ability to augment disease in an increasingly targeted manner. The use of biologics in cardiovascular disease (CVD) has steadily increased over the past several decades. Much of the early data on biologics and CVD were derived from their use in rheumatologic populations. Atherosclerosis, myocardial infarction, and heart failure have been closely linked to the inflammatory response. Accordingly, cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 have been targeted. Noninflammatory mediators, such as proprotein convertase subtilisin kexin type 9 (PCSK9), have been selected for therapeutic intervention as well. Furthermore, RNA interference (RNAi) therapy has emerged and may serve as another targeted therapeutic mechanism. Herein, we will review the history, obstacles, and advances in using biologic therapy for CVD.