Isotope labeling has contributed markedly to the success of multi-dimensional hetero-nuclear NMR spectroscopy in structure and dynamics investigations of proteins, RNAs, DNAs and their complexes. For proteins and RNAs, isotope labeling has become standard practice. In sharp contrast, isotope labeling of larger ds/ssDNAs remains a significant challenge, largely due to a lack of comparably simple, flexible and cost-efficient methods for their synthesis. Here we review isotope labeling of DNA and RNA for NMR structural studies and highlight recent progress made in the field of isotope labeling of larger ssDNA and related RNA labeling. The progress includes labeling schemes with selective deuteration as well as segmental labeling approaches.