Sequencing-based approaches now allow high-resolution, genome-scale investigation of cellular epigenetic landscapes. For example, mapping of open chromatin regions, post-translational histone modifications and DNA methylation across a whole genome is now feasible, and new non-coding regulatory RNAs can be sensitively identified via RNA sequencing. The resulting large-scale data sets promise to contribute towards a more precise and complete understanding of gene regulation and to yield insights into the interplay between genomes and the environment. In this article, I review some of the conceptual issues and currently available software tools for the analysis of sequencing-based whole-genome epigenetics data.