Nanocrystals hold great potential as parenteral delivery carrier systems for poorly water-soluble drugs. Elucidation of the in vivo fate of parenteral nanocrystals is of pharmacological, toxicological and mechanistic significance. However, it is of tremendous difficulty to monitor real-time translocation of nanocrystals in vivo owing to progressive dissolution of nanocrystals and a lack of workable tools to probe nanocrystals. In this study, self-discriminating hybrid nanocrystals (SDHNs) of a model drug curcumin (CUR) were developed by embedding traces of environment-responsive fluorescent dyes into the crystalline lattices of CUR. The SDHNs glow, but the released dyes aggregate and quench spontaneously due to the aggregation-caused quenching (ACQ) effect. Following intravenous administration into rats, a large fraction of CUR nanocrystals are cleared from blood rapidly and accumulate mainly in liver and lung. A small fraction circulate in blood for at least 48 h. Long circulating might be attributable to the surface coating with poloxamer 188, a stabilizer used during preparation; nevertheless, the ultimate fate of nanocrystals ends in reticulo-endothelial organs and tissues. It is implied that parenteral delivery provide sustained release and prolonged pharmacological efficacy, but concomitantly raise concerns of local toxicity in vital organs and tissues, especially when the active ingredients are highly toxic.