The South African smallholder GM maize experience has been—to date and internationally—the only example where a subsistence crop is produced by smallholder resource poor-farmers using GM seed. Their experience is thus of great interest, especially to African decision makers, international food and agricultural organizations, and the technology innovators. This article sheds light on eight years of research investigating the socio-economic impacts of GM maize adoption by smallholder farmers in South Africa. The main objective of the article is to highlight methodological and practical research challenges faced in this project in order to inform future socio-economic impact assessments and to contextualize research findings. Limited project findings are presented in the form of a discussion on the characteristics of early-adopting farmers and the yield impacts of GM maize adoption over the eight season period, emphasizing the variability between seasons and to show how methodological limitations impact research findings.