Cancer is the second leading cause of death worldwide. Early diagnosis and personalization of treatment have become effective routes to control the increasing mortality rate. Since cancer is a genetic disease, there is a great demand for novel techniques to detect tumor nucleic acids (NAs) with increased sensitivity. In recent years, surface enhanced Raman spectroscopy (SERS) emerged as a popular technique for biosensing in cancer theranostics. Combined with molecular probes, SERS allows ultrasensitive and multiplex detection of tumor-derived NAs, with great potential for clinical cancer detection and subtyping. In this review, we summarize and compare the various strategies for designing SERS-based NA sensors, focusing on the mechanism of sensing, followed by their representative applications to cancer theranostics in recent 5 years, as well as future challenges for clinical translation. The review is aimed to provide basic guidelines for engineering SERS-based NA sensors, according to the specific clinical cancer application.