Podophyllotoxins and epipodophyllotoxins, possess excellent activity against both drug-sensitive and drug-resistant even multidrug-resistant cancer cells via inhibition of tubulin polymerization. Several podophyllotoxin/epipodophyllotoxin derivatives such as etoposide and teniposide have already been applied for cancer therapy, revealing their potential as putative anticancer drugs. Hybridization of podophyllotoxin/epipodophyllotoxin moiety with other anticancer pharmacophores is a promising strategy to develop novel drug candidates so as to overcome drug resistance and improve the specificity, and numerous of podophyllotoxin/epipodophyllotoxin hybrids exhibit excellent in vitro antiproliferative and in vivo anticancer potency. This review emphasizes the recent development of podophyllotoxin/epipodophyllotoxin hybrids with potential application for cancer therapy covering articles published between 2010 and 2020. The mechanisms of action, the critical aspects of design as well as structure-activity relationships were also summarized.