In recent years, localized surface plasmon resonance (LSPR) spectroscopy advancements have made it a sensitive, flexible tool for probing biological interactions. Here, we describe the basic principles of this nanoparticle-based sensing technique, the ways nanoparticles can be tailored to optimize sensing, and examples of novel LSPR spectroscopy applications. These include detecting small molecules via protein conformational changes and resonance LSPR spectroscopy, as well as coupling LSPR with mass spectrometry to identify bound analytes. The last few sections highlight the advantages of single nanoparticle LSPR, in that it lowers limits of detection, allows multiplexing on the nanometer scale, and enables free diffusion of sensors in solution. The cases discussed herein illustrate creative ways that LSPR spectroscopy has been improved to achieve new sensing capabilities.