Merck’s macrocyclic PCSK9 protein-protein interaction (PPI) inhibitor, MK-0616, is a once-daily PCSK9-lowering and LDL-cholesterol-lowering small molecule that has recently demonstrated antibody-like efficacy as an oral agent in the clinic. The program highlights numerous technical achievements at the forefront of modern drug discovery, from mRNA display screening to the use of lipidic permeation enhancer formulations, and will set a standard for modern “classics in drug discovery” for some time. In this case study, we review the drug discovery campaign leading to MK-0616 from hit-finding to clinical development, highlighting why this molecule continues to be a “big deal” and a standard for modern “classics in drug discovery.”