DNA methylation plays a critical role in genome function both in health and disease. Almost 60 years after the discovery of 5-methyl cytosine and ∼25 years since the discovery that altered DNA methylation plays a role in disease, the first high-resolution DNA methylation profile (or methylome) of any genome – Arabidopsis thaliana – was determined. Although only ∼20% of the typical size of mammalian genomes, this milestone demonstrated that the methylomes of the human and similarly large genomes are now within reach. Here, we review current and emerging technologies that hold promise to deliver the first mammalian methylome and to facilitate comprehensive profiling of essentially any cell type in the context of development, disease and the environment.