14-3-3s are phosphoserine- or phosphothreonine-binding proteins, which are involved in a variety of cellular processes, including gene regulation, differentiation, cell cycle progression, and metabolism. Their mechanism of regulation is typically to induce a conformational change on the target phosphoprotein, which can alter its catalytic activity, localization within the cell, or interactions with other proteins. In addition, 14-3-3s can act as a scaffolding protein, leading to multiprotein complex formation on the target phosphoprotein. As such, 14-3-3s are integrated into a number of important phosphorylation-dependent signaling pathways. In this review, we will examine the interaction of 14-3-3 with chromatin and chromatin modifying enzymes, specifically with phosphorylated histone H3 and histone deacetyltransferases, respectively. Through diverse mechanisms, these interactions directly affect the expression of target genes, many of which are known oncogenes and lead to tumorigenesis and metastasis. Various research studies have indicated that the mechanism of 14-3-3 interaction and its role in transcription is complex and diverse, and likely involving additional components as yet undefined.