A vast range of prescribed drugs suffers from low and variable bioavailability mainly because of metabolism and permeation complications. This issue of bioavailability is a key problem that has been ongoing for many years. Various tactics have been introduced that have been quite beneficial for improving the bioavailability of poorly bioavailable drugs. Some of these tactics are targeted on cytochrome-P450 (CYP) enzymes and the permeability-glycoprotein (P-gp) efflux pump. Strategies include small-molecule inhibitors, novel drug-delivery systems, pharmaceutical synthetic excipients, and natural bioenhancers. This review discusses the role of synthetic excipients and natural bioenhancers in potentiating the activity of poorly bioavailable drugs, including their pharmacological background and their future applicability to health care. The molecules of synthetic origin such as Gelucire and those of natural origin such as quercetin and silibinin can provide noteworthy benefits to patients and the health care system by helping to reduce dosing and drug side effects.