AbstractMitochondria are important targets in diverse physiological and pathological conditions associated with cell survival and death. The characterization of mitochondria‐targeting agents is highly useful to the understanding of mitochondrial functions and the development of targeted therapeutic strategies. IR‐780, a prototypical near‐infrared (NIR) heptamethine cyanine dye, has been recently identified as the first mitochondria‐targeting multifunctional NIR dye, it has excellent optical imaging and therapeutic properties and is receiving increasing attention in the field of NIR theranostic applications. Although the targeting mechanisms of IR‐780 dye remain to be fully identified, emerging studies have shown that the targeting process is glycolysis dependent. Therefore, it may represent a new tool to further understand and advance the field of mitochondrial medicine and glycolytic metabolism. Several types of nanostructures also have been developed to encapsulate and deliver IR‐780 dye and its derivatives for therapeutic purposes to improve their bioavailablity and potential toxicity. IR‐780 dye and its derivatives have broadened the concept of targeted imaging and therapy and have shown promise in potential applications. In consideration of the urgent need and rapid development of targeted theranostics, the recent progress on the synthesis, mechanisms of actions, and potential applications of IR‐780‐based heptamethine dyes and nanostructures for multimodal targeted imaging and therapy is reviewed.