We review the current understanding of the mechanics of DNA and DNA-protein complexes, from scales of base pairs up to whole chromosomes. Mechanics of the double helix as revealed by single-molecule experiments will be described, with an emphasis on the role of polymer statistical mechanics. We will then discuss how topological constraints— entanglement and supercoiling—impact physical and mechanical responses. Models for protein–DNA interactions, including effects on polymer properties of DNA of DNA-bending proteins will be described, relevant to behavior of protein–DNA complexes in vivo. We also discuss control of DNA entanglement topology by DNA-lengthwise-compaction machinery acting in concert with topoisomerases. Finally, the chapter will conclude with a discussion of relevance of several aspects of physical properties of DNA and chromatin to oncology.