Nuclear magnetic resonance (NMR) spectroscopy represents an indispensable analytical tool for the structural and functional characterization of complex molecular mixtures, with significant applications in metabolomics, natural product discovery, and pharmaceutical analysis. A primary advantage of NMR is its capacity for the direct analysis of complex matrices, such as synthetic libraries and crude natural extracts, obviating the need for extensive chromatographic fractionation and thereby enabling the direct identification of bioactive constituents. This perspective provides a comprehensive review of ligand-observed NMR methodologies based on the principle that molecular binding is a prerequisite for biological function. Key techniques are systematically described, including Saturation Transfer Difference (STD), Transferred-NOE SpectroscopY (trNOESY), and methods based on relaxation rates (e.g., T2-relaxation filtering using CPMG pulse sequences). Further approaches include Diffusion Ordered SpectroscopY (DOSY), WaterLOGSY, and 19F NMR spectroscopy, a highly sensitive modality for screening fluorinated compound libraries. Collectively, these techniques facilitate the rapid identification of binding hits and provide critical insights into the structural and dynamic features of ligand–receptor interactions, including binding epitopes and bound-state conformations. The paper envisages future perspectives, emphasizing the potential of hyperpolarization methods to overcome the sensitivity limitations of benchtop instruments and the growing importance of in-cell and on-cell NMR applications for investigating molecular interactions within a native physiological context, which constitutes a significant frontier in drug discovery.