Macrocyclic compounds, which are defined by ring structures containing 12 or more atoms, occupy a unique position at the intersection of small molecules and biologically active drugs. Their distinctive properties, including improved biological activity and selectivity, have made them a subject of intense interest in pharmaceutical research. These compounds hold a promise for advancing drug discovery and offer exciting opportunities for the development of novel therapeutic agents. This chapter provides an in-depth exploration of the theoretical foundation of macrocyclic drug design, including their origin, classification, and various advantages. A total of 24 Food and Drug Administration-approved macrocyclic drugs from 2010 to 2022 were collected to provide insights into their clinical relevance. In addition, current research trends in macrocyclic compounds were examined, focusing on their chemical properties, macrocyclization strategies, and library screening methodologies. Practical examples were provided to highlight their impact, including the macrocyclization of proteolysis targeting chimeras and the artificial intelligence-driven design of Janus kinase 2 inhibitors using Macformer. These case studies illustrate how macrocyclic compounds are driving advancements in drug design and paving the way for innovative therapeutic developments.