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© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) ; An intriguing and remarkable feature of African trypanosomes is their antigenic variation system, mediated by the variant surface glycoprotein (VSG) family and fundamental to both immune evasion and disease epidemiology within host populations. Recent studies have revealed that the VSG repertoire has a complex evolutionary history. Sequence diversity, genomic organization, and expression patterns are species-specific, which may explain other variations in parasite virulence and disease pathology. Evidence also shows that we may be underestimating the extent to what VSGs are repurposed beyond their roles as variant antigens, establishing a need to examine VSG functionality more deeply. Here, we review sequence variation within the VSG gene family, and highlight the many opportunities to explore their likely diverse contributions to parasite survival. ; S.S.P. is funded by the European Union's Horizon 2020 research and innovation program through a Marie Skłodowska-Curie Individual Standard European Fellowship , under grant agreement no. 839960 . A.P.J. is funded by a Leverhulme Trust Research Fellowship ( RF-2020-413 ). L.M.F. is an Investigator CEEC of the Fundação para a Ciência e a Tecnologia ( CEECIND/03322/2018 ) and the laboratory is funded by the ERC (FatTryp, ref. 771714 ). ; info:eu-repo/semantics/publishedVersion