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With the continuous growth of the human population and new challenges in the quality of life, it is more important than ever to diagnose diseases and pathologies with high accuracy, sensitivity and in different scenarios from medical implants to the operation room. Although conventional methods of diagnosis revolutionized healthcare, alternative analytical methods are making their way out of academic labs into clinics. In this regard, surface-enhanced Raman spectroscopy (SERS) developed immensely with its capability to achieve single-molecule sensitivity and high-specificity in the last two decades, and now it is well on its way to join the arsenal of physicians. This review discusses how SERS is becoming an essential tool for the clinical investigation of pathologies including inflammation, infections, necrosis/apoptosis, hypoxia, and tumors. We critically discuss the strategies reported so far in nanoparticle assembly, functionalization, non-metallic substrates, colloidal solutions and how these techniques improve SERS characteristics during pathology diagnoses like sensitivity, selectivity, and detection limit. Moreover, it is crucial to introduce the most recent developments and future perspectives of SERS as a biomedical analytical method. We finally discuss the challenges that remain as bottlenecks for a routine SERS implementation in the medical room from in vitro to in vivo applications. The review showcases the adaptability and versatility of SERS to resolve pathological processes by covering various experimental and analytical methods and the specific spectral features and analysis results achieved by these methods.