<p>Surface plasmon resonance (SPR) is a widely adopted and highly informative biophysical technique in fragment-based drug discovery, enabling the detection and characterization of weak and transient molecular interactions that initiate the progression from fragments to lead compounds. Owing to its sensitivity, low sample consumption, and compatibility with both direct-binding and functional assay formats, SPR plays a central role within integrated fragment discovery workflows, supporting affinity estimation, hit validation, and mechanistic interrogation when applied with appropriate experimental design. Recent advances in sensor-chip chemistries, buffer and solvent optimization, clean-screening strategies, and high-throughput instrumentation have further enhanced the robustness and reliability of SPR-based fragment assays. When combined with complementary biophysical and structural approaches, including thermal shift analysis, calorimetry, mass spectrometry, thermophoresis, NMR spectroscopy, X-ray crystallography, and cryo-electron microscopy, SPR contributes to a multidimensional validation framework that enables informed hit triage, structural interpretation, and structure-guided optimization. This review provides a practical guide to the use of SPR in fragment-based discovery, covering conceptual principles, experimental design, data analysis strategies, and best practices for minimizing artifacts and improving data quality. Beyond technical considerations, SPR illustrates a broader principle of molecular discovery: even weak interactions, when measured rigorously and interpreted in context, can yield insights that guide the transformation of fragment hits into biologically meaningful and therapeutically relevant molecules.</p>