Here, system analysis of SFDI highlights the depth selectivity of this planar acquisition geometry and explores the limitations of its contrast-detail resolution, model-data goodness of fit evaluated in surgical breast tissues, and the accuracy of optical parameter quantification. In the spatial frequency domain, effective attenuation, and consequently probing depth, , is a product of both the effective attenuation coefficient, , and the illumination modulation frequency, , such that . Consequently, light is attenuated more rapidly at high spatial frequencies yielding superficial interrogation of the specimen. At high spatial frequencies, the transport coefficient, , is the primary source of optical contrast. In the diffusion limit, this is predominantly a scattering signature. Sampling with a modulation frequency up to , we demonstrated an ability to detect up to 33% scattering contrast at the maximum depth relevant to surgical margin assessment (1.5 mm). The analytical solution to the diffusion approximation in the spatial frequency domain1 reveals that reflectance behaves as an inverse function of the ratio, . Consequently, at low spatial frequencies, absorption dominates optical contrast and there is a relatively deeper interrogation depth. The camera resolution and the number of sources (or spatial frequencies projected per sample) additionally influence detectable contrast. Finally, absolute quantification of optical parameters requires a repeatable, stable calibration phantom with known optical properties and all measures must be made at a uniform height because the reflectance amplitude decays according to an inverse square law. A three-phase amplitude de-modulation scheme has been developed to correct for surface profile changes,49 but continued efforts are needed to standardize calibration phantoms across institutions.