The optically transparent biological window in the near-infrared (NIR) spectral range allows deep-tissue excitation and the detection of fluorescence signals. Spectrum-domain discrimination of NIR contrast agents via an upconversion or downshifting scheme requires sufficient (anti-) Stokes shift to separate excitation and fluorescence emission. Here, we report a time-domain (τ) scheme in which >5,000 ytterbium signal transducers are condensed within an optically inert and biocompatible CaF2 shell (2.3 nm), which forms a 14.5 nm τ-dot. Because of the long-lived and spectrally narrowly defined excited state of pure ytterbium ions, the NIR τ-dot can convert the NIR pulsed excitation into long-decaying luminescence with an efficiency approaching 100%. Within a safe injection dosage of 13 μg g-1 , an excitation power density of 1.1 mW cm-2 was sufficient to image organs with a signal-to-noise ratio of >9. The high brightness of τ-dots further allows long-term in vivo passive targeting and dynamic tracking in a tumour-bearing mouse model. To learn more about this work, please use the following link https://www.nature.com/articles/s41566-019-0437-z.