Optical imaging, providing physiologically specic optical absorption, scattering, polarization, and molecular contrasts with nonionizing radiation, is a promising tool for medical diagnosis. Moreover, it complements the established nonoptical clinical modalities (e.g., magnetic resonance imaging, x-ray computed tomography, positron emission tomography, and ultrasound imaging) by providing insights at the cell and organelle levels (Figure 11.1). However, in vivo optical imaging is challenging due to strong tissue scattering and absorption. ere are two fundamental depth limits for pure optical imaging. e rst is near one transport mean free path (TMFP), the depth dimension of the quasiballistic regime in biological tissues (~1 mm; yellow dashed line in Figure 11.1).1 To reach the depth of one TMFP, incident photons may undergo as many as tens of scattering events, which disable eective optical focusing. us, TMFP presents as the soft depth limit (also called the diusion limit) for all ballistic optical microscopy (e.g., confocal microscopy, two-photon microscopy [TPM], and optical coherence tomography [OCT]). e second depth limit is around 5-7 cm (red dashed line in Figure 11.1), which corresponds to a 43 dB one-way decay in light intensity.1 Beyond this limit, referred to as the hard depth limit for all optical imaging modalities, there are simply not enough photons to provide sucient signal-to-noise ratio.