Podophyllotoxin is an aryltetralin lignan synthesized in several plant species, which is used in chemotherapies for cancers and tumor treatment. More potent semisynthetic derivatives of podophyllotoxin such as etoposide and teniposide are being developed and evaluated for their efficacy. To meet the ever increasing pharmaceutical needs, species having podophyllotoxin are uprooted extensively leading to the endangered status of selective species mainly Sinopodophyllum hexandrum. This has necessitated bioprospection of podophyllotoxin from different plant species to escalate the strain on this endangered species. The conventional and non-conventional mode of propagation and bioprospection with the integration of biotechnological interventions could contribute to sustainable supply of podophyllotoxin from the available plant resources. This review article is focused on the understanding of different means of propagation, development of genomic information, and its implications for elucidating podophyllotoxin biosynthesis and metabolic engineering of pathways. In addition, various strategies for sustainable production of this valuable metabolite are also discussed, besides a critical evaluation of future challenges and opportunities for the commercialization of podophyllotoxin.