With rapid technological advancements emerging epigenetic studies of complex traits have shifted from candidate gene analyses towards epigenome-wide association studies (EWAS). EWAS aim to systematically identify epigenetic variants across the genome that associate with complex phenotypes. Recent EWAS using case–control and disease-discordant identical twin designs have identified phenotype-associated differentially methylated regions for several traits. However, EWAS still face many challenges related to methodology, design and interpretation, owing to the dynamic nature of epigenetic variants over time. This article reviews analytical considerations in conducting EWAS and recent applications of this approach to human aging and age-related complex traits.