AbstractDetermining cell identity and maturation status of differentiated pluripotent stem cells (PSCs) requires knowledge of the transcriptional and epigenetic trajectory of organs during development. Here, we generate a transcriptional and DNA methylation atlas covering 21 organs during human fetal development. Analysis of multiple isogenic organ sets shows that organ-specific DNA methylation patterns are highly dynamic between week 9 (W9) and W22 of gestation. We investigate the impact of reprogramming on organ-specific DNA methylation by generating human induced pluripotent stem cell (hiPSC) lines from six isogenic organs. All isogenic hiPSCs acquire DNA methylation patterns comparable to existing hPSCs. However, hiPSCs derived from fetal brain retain brain-specific DNA methylation marks that seem sufficient to confer higher propensity to differentiate to neural derivatives. This systematic analysis of human fetal organs during development and associated isogenic hiPSC lines provides insights in the role of DNA methylation in lineage commitment and epigenetic reprogramming in humans.