Clathrate compounds traditionally were discovered by happy accident because of the considerable difficulty in predicting and controlling weak intermolecular forces in crystal engineering. This chapter surveys and analyzes the various approaches taken to obtain synthetic organic clathrates, ranging from modification of a known lead compound to the design of an entirely new host from first principles. The clathrate literature has been categorized into a series of recognizable families. The individual members of these families have certain structural characteristics that define their membership. These common features are described and their functions are analyzed in supramolecular terms. Once identified, these key characteristics can then be retained during the synthesis of new family members. A number of clathrand hosts are known that contain structural features associated with two or more of the basic clathrate families. These compounds are described and their relationship with multiple host families is delineated. Finally, the chapter examines the current state of play in this research area. Recent advances and current difficulties are highlighted.