Fluorescence imaging across the near-infrared (NIR, 700–1000 nm) and shortwave infrared (SWIR, 1000–2000 nm) regions offers significant advantages for biomedical applications. Over the past decade, we have advanced a unique class of fluorophores–deemed fluorofluorophores–that are soluble in the fluorous phase. The unique properties of the fluorous phase, including low polarizability and high oxygen content, render this medium challenging for fluorophore brightness and photostability.