Atoms at specific “key” positions along the ring of a group of -membered ring macrocycles can govern its shape, or “topology”. The driving force for the organization of the structures is the minimization of steric strain on groups attached to the key atoms. When the key atom is a stereocenter, a macrocycle with planar chirality is observed. The key positions can work in a coordinated fashion to guide one topology over another. X-ray crystal structures of representative -macrodiolides served as the basis of the structural observations made. The results provide a framework for the design of new macrocycles with well-defined structures as well as for understanding some general principles that influence the topology of natural product macrocycles.