The cinnamamide (cinnamic acid amide and cinnamide) is a privileged scaffold present widely in a number of natural products. The scaffold acts as a useful template for designing and arriving at newly drug-like molecules with potential pharmacological activity. An attempt has been made to review the extensive occurrence of cinnamamide scaffold in many lead compounds reported for treating various diseases, their binding interactions with the therapeutic targets as well as mechanism of action and their structure-activity relationships. The discoveries of cinnamamide systems and some examples of unusual cinnamamides having an aromatic, aliphatic, and heterocyclic or other rings condensed to the basic cinnamamide structure also have been extensively covered in this review.