During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.