Holding the Harry S. Mosher Professorship of Chemistry at Stanford University, with a courtesy appointment in applied physics, William E. Moerner opened an entire branch of measurement science: watching one molecule at a time. The American chemical physicist is recognized as the first person ever to optically detect and spectroscopically study a single molecule in a condensed phase, a feat he accomplished in 1989 while working at the IBM Almaden Research Center. Decades later that line of work was honored with a one-third share of the 2014 chemistry Nobel for super-resolved fluorescence microscopy, alongside Eric Betzig and Stefan Hell. Before this, every optical measurement blurred together vast crowds of molecules, hiding how any one of them actually behaves; Moerner's breakthrough founded the discipline of single-molecule spectroscopy and exposed surprising heterogeneity among supposedly identical molecules. He subsequently proved that the fluorescence of individual green fluorescent protein molecules could be toggled on and off — the conceptual key that later made single-molecule-based super-resolution imaging schemes like PALM possible. From IBM Almaden to UC San Diego and finally Stanford, Moerner has aimed single-molecule techniques at questions spanning biophysics, photophysics, and materials science — among them an anti-Brownian trap that holds and tracks one freely diffusing biomolecule in solution or inside a living cell long enough to study it. Today these methods anchor a broad swath of fundamental research and have rippled outward into pharmaceutical assay design and next-generation optical instrumentation.