Cytosine methylation in mammals is an epigenetic modification required for viability of the developing embryo. It has been suggested that DNA methylation plays important roles in X-chromosome inactivation, imprinting, protection of the genome from invasive DNA sequences, and compartmentalization of the genome into active and condensed regions. Despite the significance of DNA methylation in mammalian cells, the mechanisms used to establish methylation patterns during development are not understood. This review will summarize the current state of knowledge about potential roles for cis- and trans-acting factors in the formation of methylation patterns in the mammalian genome.