The combination of stem cell models and epigenomics in studies of the role of non-coding mutations in human disease. Epigenomic analyses of cells derived through in vitro stem cell differentiation models can be used to define the functional regulatory space, or 'regulatome', of a given cell type and to study the significance of the non-coding genetic variation in human disease. (a) The vast non-coding fraction of the human genome can be significantly reduced by defining the regulatome of a given cell type via epigenomic profiling of chromatin signatures that define different types of regulatory elements, such as enhancers, promoters and insulators. Regulatome maps obtained in the disease-relevant cell types define genomic space that can be subsequently searched for the recurrent disease-associated genetic variants. (b) Most genetic variants associated with complex human diseases appear to reside in non-coding regions of the human genome. To assess functional consequences of such variants, disease-relevant cell types can be derived from healthy and disease-affected donor induced pluripotent stem cells (iPSCs) and epigenomic profiling can be used to evaluate how these genetic variants affect chromatin signatures, and transcription factor and coactivator occupancy at regulatory elements. CTCF, CCCTC-binding factor, insulator associated protein; ESC, embryonic stem cell; H3K4me1, methylation of lysine 4 of histone H3; H3K4me3, trimethylation of lysine 4 of histone H3; H3K27ac, acetylation of lysine 27 of histone H3; H3K27me3, trimethylation of lysine 27 of histone H3; meC, methylcytosine.