Experimental screening for protein-ligand interactions is a central task in drug discovery. Nuclear magnetic resonance (NMR) spectroscopy enables the determination of binding affinities, as well as the measurement of structural and dynamic parameters governing the interaction. With traditional liquid-state NMR relying on a nuclear spin polarization on the order of 10-5, hyperpolarization methods such as dissolution dynamic nuclear polarization (D-DNP) can increase signals by several orders of magnitude. The resulting increase in sensitivity has the potential to reduce requirements for the concentration of protein and ligands, improve the accuracy of the detection of interaction by allowing the use of near-stoichiometric conditions, and increase throughput. This chapter introduces a selection of basic techniques for the application of D-DNP to screening. Procedures for hyperpolarization are briefly reviewed, followed by the description of NMR methods for detection of binding through changes in chemical shift and relaxation parameters. Experiments employing competitive binding with a known ligand are shown, which can be used to determine binding affinity or yield structural information on the pharmacophore. The specific challenges of working with nonrenewable hyperpolarization are reviewed, and solutions including the use of multiplexed NMR detection are described. Altogether, the methods summarized in this chapter are intended to allow for the efficient detection of binding affinity, structure, and dynamics facilitated through substantial signal enhancements provided by hyperpolarization.