Surface-enhanced Raman spectroscopy (SERS) has demonstrated potential for various biomedical applications. However, when these sensors/substrates are exposed for analysis of complex biological fluids, their sensitivity is gradually decreased due to fouling of proteins on the plasmonic substrates, leading to hotspot blockade. To overcome this limitation, immense efforts have been devoted in recent times to develop stealth SERS substrates to maintain sensing capabilities in clinical samples. Two important methods have been proposed for developing stealth SERS with the use of zwitterionic molecules and nanoshearing force. These stealth modification strategies help reduce the background noise and enhance the sensing capability with their antifouling features for point-of-care-testing (POCT). Additionally, we have highlighted some of the recent SERS developments that demonstrate reliable stealth and sensitivity when employed for diagnosis or personalized treatment. Herein, we concisely review and discuss the future of SERS for investigations in complex clinical samples.