Sesame (Sesamum indicum L.) is a significantly lucrative cash crop for millions of small-holder farmers. Its seeds are an important source of a highly appreciated vegetable oil globally and two clinically essential antioxidant lignans, sesamin and sesamolin. Accordingly, many countries import millions of tons of sesame seed every year. The demand for lignan-rich sesame seeds has been increasing in recent years due to the continuous discovery of several pharmacological attributes of sesamin and sesamolin. To meet this demand, the sesame breeder's primary objective is to release sesame cultivars that are enriched in oil and lignans. Thus, it is necessary to summarize the information related to the sesamin and sesamolin contents in sesame in order to promote the joint efforts of specialized research teams on this important oilseed crop. In this article, we present the current knowledge on the sesamin and sesamolin contents in S. indicum L. with respect to the updated biosynthesis pathway, associated markers, governing loci, available variability in sesame germplasm, the in planta potential roles of these compounds in sesame, and the newly discovered pharmacological attributes. In addition, we propose and discuss some required studies that might facilitate genomics-assisted breeding of high lignan content sesame varieties.