The 1,5-benzothiazepine ring system is an important pharmacophore in medicinal chemistry and modern drug discovery. 1,5-benzothiazepine and its derivatives are used in organic synthesis and they are used in evaluating new product that possesses different biological activities. The first molecule of 1,5-benzothiazepine used clinically was diltiazem, followed by clentiazem, for their cardiovascular action. Some of the 1,5-benzothiazepine derivatives were also used clinically for CNS disorders which includes thiazesim, clothiapine and quetiapine. Therefore, the 1,5-benzothiazepines are useful compounds in the drug research which has stimulated the invention of a wide range of synthetic methods for their preparation and chemical transformations. This review article covers the most active 1,5-benzothiazepine derivatives and discusses the structure-activity relationship of the most potent compounds. It can act as an important tool for medicinal chemists to develop newer compounds possessing 1,5-benzothiazepine moiety that could be better agents in terms of efficacy and safety.