The rapid quantification of antimicrobial agents is important for therapeutic drug monitoring (TDM), enabling personalized dosing schemes in critically ill patients. Highly sophisticated TDM technology is becoming available, but its implementation in hospitals is still limited. Among the various proposed techniques, surface-enhanced Raman scattering (SERS) stands out as one of the more interesting due to its extremely high sensitivity, rapidity, and fingerprinting capabilities. Here, we present a comprehensive review of various SERS-based novel approaches applied for direct and indirect detection and quantification of antibiotic, antifungal, and antituberculosis drugs in different matrices, particularly focusing on the challenges for successful exploitation of this technique in the development of assays for point-of-care tests.