In previous chapters, we have described how the expression of genes into final products, the functional proteins, is regulated at multiple stages. These complex and multidimensional processes mediate responses to environmental and developmental signals. One of the critical biological phenomena, cell differentiation, is primarily underpinned by the expression of select genes. The commitment of higher potency cells, totipotent, pluripotent, and multipotent, to differentiated cells of restricted potency, defines cell differentiation. The regulation of gene expression lies at the heart of cell differentiation. The gene regulatory networks formed by multiple transcription factors make the initial commitment to a cell lineage, which is then further stabilized by epigenetic modification, thus restricting the group of genes to be expressed, leading to cells of lower potency or terminally differentiated cells. Many events disrupt the process of gene regulation. Mutations in critical regulatory genes are often responsible for dysregulation of gene expression that may have pathological consequences. Mutations in TFs and chromatin modifiers are a significant source of dysregulation of gene expression and are the underlying cause of many diseases. Apart from mutations, other changes may also lead to dysregulation of gene expression. Metabolic changes may be an important source of dysregulation. Several processes regulate chromatin modifications, of which metabolism is an important one. Metabolic processes and metabolites have emerged as key elements in regulating PTMs, and this link is imbalanced or disrupted in many diseases. This chapter also discusses how the effects of dysregulation can be mitigated using externally delivered molecules, which form the basis of many therapeutic strategies.