In eukaryotes, the packaging of DNA and proteins, termed chromatin, is an essential determinant of transcription. The basic unit of chromatin, the nucleosome, is composed of ∼146 base pairs of DNA spooled around a dense protein core containing two copies each of histones H2A, H2B, H3, and H4. These histone proteins are highly conserved and possess tails, which extend and interact with DNA. Covalent modifications that alter the charge of the histone tail are believed to influence their electrostatic interaction with DNA and act as interaction surfaces for epigenetic effectors that influence the level of chromatin compaction and accessibility to the transcriptional apparatus. Less-compacted chromosomal regions, euchromatin, tend to be gene rich and transcriptionally active. In contrast, condensed constitutive heterochromatin plays an essential function in chromosomal integrity and structural regions such as the centromere and telomere. Facultative heterochromatin plays an essential role by imposing the differentiation-specific transcriptional regulation required to underpin cellular identity. Long noncoding RNAs (lncRNAs) are emerging as key transcriptional regulators, which cooperate with the polycomb repressive complexes and the heterochromatin apparatus in differentiation. Unsurprisingly, disruption of this key pathway is now recognized to play important roles in carcinogenesis and metastases. In this chapter, we review current understanding of the normal and oncogenic functions of lncRNAs, polycomb, and heterochromatin.