Molecule-surface interactions and processes are at the heart of many technologies, including heterogeneous catalysis, organic photovoltaics, and nanoelectronics, yet they are rarely well understood at the molecular level. Given the inhomogeneous nature of surfaces, molecular properties often vary among individual surface sites, information that is lost in ensemble-averaged techniques. In order to access such site-resolved behavior, a technique must possess lateral resolution comparable to the size of surface sites under study, analytical power capable of examining chemical properties, and single-molecule sensitivity. Tip-enhanced Raman spectroscopy (TERS), wherein light is confined and amplified at the apex of a nanoscale plasmonic probe, meets these criteria. In ultrahigh vacuum (UHV), TERS can be performed in pristine environments, allowing for molecular-resolution imaging, low-temperature operation, minimized tip and molecular degradation, and improved stability in the presence of ultrafast irradiation. The aim of this review is to give an overview of TERS experiments performed in UHV environments and to discuss how recent reports will guide future endeavors. The advances made in the field thus far demonstrate the utility of TERS as an approach to interrogate single-molecule properties, reactions, and dynamics with spatial resolution below 1 nm.