Surface-enhanced Raman spectroscopy (SERS) is a powerful analytical technique, which allows quantitative detection of chemical species with molecular specificity and single-molecule sensitivity. These useful properties can be further combined with portable Raman spectrometers which allow SERS to be potentially employed at the point-of-care. As a result, SERS has found a wide range of potential applications in both real-life chemical analysis and fundamental mechanistic studies. Despite these advantages, true applications of SERS have been limited due to its high cost, which arises mainly from the fact that SERS relies on expensive single-use Ag/Au enhancing substrates suitable only for the analysis of pure samples. A viable approach to address this issue is to develop multifunctional SERS substrates, which in addition to providing Raman signal enhancement, is armed with other practical functionalities that simplifies the analysis and/or allows the substrate to be regenerated for repeated use. This review gives an account of the recent progress in the fabrication of multi-functional SERS substrates, namely flexible, separation-enhancement-in-one, calibration-enhancement-in-one and regeneration-enhancement-in-one substrates. Specific focus is placed on summarizing and discussing the most widely used strategies to incorporate each type of functionality and their respective advantages and drawbacks. Finally, we present our perspectives on the future challenges and potential opportunities in the development of smart multifunctional SERS sensors for achieving sustainable and wide-spread application of SERS.