Thanks to improvements in instrumental sensitivity as well as the development of a suite of new experiments, 13C direct detection NMR offers a useful tool for biomolecular applications. It can generally be applied in parallel to proton-detected NMR, providing additional and complementary data. In a variety of cases, as a result of the intrinsically different properties of the heteronuclei with respect to proton nuclei, it also enables the recovery of information that is lost or difficult to access through proton detection. This chapter addresses the several areas of biomolecular NMR where experiments based on 13C direct detection are particularly useful. The entire experimental NMR strategy, the key instrumental aspects, and the general procedures for the setup of NMR experiments are outlined.