Macrocyclic compounds (MCs) -small molecules that contain a ring of 12 or more atoms -are a recurring theme among drugs that have been developed from natural products. For example, seven of the nine natural products with molecular weights above 500 Da. that led to approved drugs during the 35 years from 1970-2006 are MCs. Overall, there are at least 102 approved drugs and clinical candidates that are MCs, of which 42 show significant systemic distribution after oral administration. A large proportion of oral MC drugs have a high molecular weight, or otherwise violate conventional notions of druglikeness such as are embodied in Lipinski's Rule of 5 (Ro5) or Veber's Rules. This observation has led to the hypothesis that a macrocyclic structure can confer favorable pharmaceutical properties, including oral bioavailability, compared to acyclic compounds of similar size and composition. Consequently, there has been great interest in the potential utility of MCs as drugs, especially for modulation of traditionally challenging targets such as protein-protein interactions, where a high molecular weight enabling a large area of contact with the target protein might be required for strong binding. In addition to increased binding affinity, other advantages that have been associated with a macrocyclic structure include increased selectivity, and ADME properties such as enhanced metabolic and serum stability and ultimately oral bioavailability. Systematic analysis of the extent to which each of these benefits is achieved in practice is rare, however.