The combinatorial number of possible methylomes in biological time and space is astronomical. Consequently, the computational analysis of methylomes needs to cater for a variety of data, throughput and resolution. Here, we review recent advances in 2 nd generation sequencing (2GS) with a focus on the different methods used for the analysis of MeDIP-seq data. The challenges and opportunities presented by the integration of methylation data with other genomic data types are discussed as is the potential impact of emerging 3 rd generation sequencing (3GS) based technologies on methylation analysis.