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The occurrence of efflux mechanisms via Permeability-glycoprotein (P-gp) recognized as an important physiological process impedes drug entry or transport across membranes into tissues. In some instances, either low oral bioavailability or lack of brain penetration has been attributed to P-gp mediated efflux activity. Therefore, the objective of development of P-gp inhibitors was to facilitate the attainment of higher drug exposures in tissues. Many third-generation P-gp inhibitors such as elacridar, tariquidar, zosuquidar, etc. have entered clinical development to fulfil the promise. The body of evidence from in vitro and in vivo preclinical and clinical data reviewed in this paper provides the basis for an effective blockade of P-gp efflux mechanism by elacridar. However, clinical translation of the promise has been elusive not just for elacridar but also for other P-gp inhibitors in this class. The review provides …