Hepatitis C virus (HCV) is estimated to have chronically infected over 175 million people worldwide, causes serious damage to the histology and function of the liver over the course of 20‐30 years, gradually progressing to organ failure in a subset of the cases. After an extensive medicinal chemistry optimization campaign that involved evolving chemotypes with molecular properties at the boundaries of the chemical space traditionally considered to be drug‐like, Bristol‐Myers Squibb (BMS) scientists discovered the highly potent and first‐in‐class NS5A replication complex inhibitor daclatasvir (DCV, 1). Two additional NS5A inhibitors, ledipasvir (4) and ombitasvir (5), have also been approved for marketing in combination with other direct‐acting antiviral agents (DAAs). This chapter discusses key aspects of the discovery and development campaigns that produced DCV along with select highlights from mode of action studies.