Human pluripotent stem cell (hPSC) technology offers wide potential for regenerative medicine, in vitro modelling of complex disease, and mapping developmental trajectories. In particular, hPSC technology in neurodegenerative disease research drives promising advances in cell replacement therapy and facilitates analysis of sparse neural populations. Key to the versatility and promise of hPSC technology is the exquisite genetic control available in human in vitro culture systems. Whereas gene targeting has enabled transgenic mouse models of human disease [6], hPSC technology, specifically patient-derived induced pluripotent stem cells (hiPSCs), enables renewable culture of human tissue that contains putative and novel disease-associated mutations (DAMs). By differentiating hiPSCs toward neural cell fates, the pathogenic role of DAMs can be investigated in cell-specific context. However, hPSC differentiation protocols require long-term culture, which is incompatible with techniques that transiently modulate gene expression by expressing transgenes from episomes. Toward facilitating genetic manipulation in hPSCs, we tailored a technology for targeted transgenesis, recombinase-mediated cassette exchange (RMCE), to simplify and direct genomic integration of transgenes in hPSCs.