The benzoxazole heterocycle is often found in ligands targeting a plethora of receptors and enzymes. By analysis of published X-ray structures, this review aims at highlighting key interactions which the benzoxazole may engage in with its host protein. Furthermore, bioavailability, metabolism and the use of benzoxazole as a bioisostere are discussed. The review is extended to cover structure-activity relationship studies of 2-substituted benzoxazoles, 2-substituted oxazolopyridines, and in perspective, application of the recently published novel heterocycle oxazolopyrazine in medicinal chemistry studies.