Small molecule metabolites depict a biological system's status and help monitor disease conditions. Surface‐enhanced Raman scattering (SERS) holds considerable promise as an instant and non‐destructive detection tool for biological diagnosis. With single‐molecular sensitivity, molecular fingerprint and water compatible, SERS provides valuable information about chemical structures and analyte compositions, especially desirable in biological diagnosis. Design and fabrication of effective, stable SERS substrates can be one of the major research priorities to provide small‐molecule tracing with high sensitivity, selectivity, and reproducibility. Significant efforts have been directed towards creating high‐performance and multifunctional SERS substrates spanning from coinage metals to semiconductor materials. However, most SERS substrates are suffering from unsatisfied sensitivity for tracing small molecules such as volatile organic compounds (VOCs) and other biomarkers. This review summarized recent advances in SERS‐active substrates and their sensing for small biomarker molecules, especially VOCs in diagnosis.