Controlling the functional dynamics of DNA within living cells is essential in biomedical research. Epigenetic modifications such as DNA methylation play a key role in this process. Controlled DNA methylation editing can be attained via genetic means. Yet there are few chemical tools available for the spatial and temporal modulation of this modification. Here we present a small-molecule approach to modulate DNA methylation with light. The strategy uses a photo-tuneable version of a clinically used drug (5-aza-2-deoxycytidine) to alter the catalytic activity of DNA methyltransferases, the enzymes that methylate DNA. After uptake by cells, the photo-regulated molecule can be light-controlled to reduce genome-wide DNA methylation levels in proliferating cells. The chemical tool complements genetic, biochemical and pharmacological approaches to study the role of DNA methylation in biology and medicine.