Transcription factors, chromatin and chromatin-modifying enzymes are key components in a complex network through which the genome interacts with its environment. For many transcription factors, binding motifs are found adjacent to the promoter regions of a large proportion of genes, requiring mechanisms that confer binding specificity in any given cell type. These include association of the factor with other proteins and packaging of DNA, as chromatin, at the binding sequence so as to inhibit or facilitate binding. Recent evidence suggests that specific post-translational modifications of the histones packaging promoter DNA can help guide transcription factors to selected sites. The enzymes that put such modifications in place are dependent on metabolic components (e.g. acetyl CoA, S-adenosyl methionine) and susceptible to inhibition or activation by environmental factors. Local patterns of histone modification can be altered or maintained through direct interaction between the transcription factor and histone modifying enzymes. The functional consequences of transcription factor binding are also dependent on protein modifying enzymes, particularly those that alter lysine methylation at selected residues. Remarkably, the role of these enzymes is not limited to promoter-proximal events, but can be linked to changes in the intranuclear location of target genes. In this review we describe results that begin to define how transcription factors, chromatin and environmental variables interact and how these interactions are subverted in cancer. We focus on the nuclear receptor family of transcription factors, where binding of ligands such as steroid hormones and dietary derived factors provides an extra level of environmental input.