Macrocycles are Great Cycles. This was the title of a review we wrote in 2011 to reflect the increasing attention being then given by medicinal chemists toward this unique compound class. Six years later, the interest has only grown, which strongly indicates that the macrocycle field is not just another trend that becomes hot, generates frenetic activity, then rapidly vanishes or dissipates into irrelevance—quite the contrary. Macrocycles of very diverse chemical classes continue to generate a high level of interest from the drug discovery community, with an impressive number already in or entering the clinic. When we started working over 15 years ago at one of the pioneering companies in this area, NéoKimia (later Tranzyme Pharma), formed to realize the vision of Prof. Pierre Deslongchamps regarding libraries of conformationally defined and chemically diverse macrocyclic molecules, there was only one other company (Polyphor)primarily focused on using macrocycles for drug discovery purposes, and few academics had research focused on these structures. At the time, we met with considerable skepticism that such molecules could ever be effective synthetic drugs. Now, that situation has changed dramatically, with over 30 companies involved in pursuing macrocycles as a key aspect of their R&D, while the number of scientific papers on the topic has exploded .As a result, we felt it would be very timely to assemble a reference book on the medicinal chemistry of macrocycles. From the onset, we wanted this to be a practical guide targeting both experts and their teams, as well asneophytes.