Near-Infrared Spectroscopy (NIRS) is a non-invasive, portable, and cost-effective technique that is widely used in the biomedical field to investigate the hemodynamics and oxygenation levels of a variety of biological tissues. To achieve a penetration depth of centimeters, NIRS employs wavelengths in the near-infrared spectral region (typically 650-900 nm). However, non-invasive measurements performed with NIRS are affected by two common problems: (1) the strong sensitivity to hemodynamic contributions from superficial layers, which may confound the measurements of targeted hemodynamics in deeper tissue; (2) artifacts originating from instrumental effects and from subject movements, which may limit practical applicability and clinical use. Over time, different instrumental and methodological approaches have been proposed to address these problems and increasingly sophisticated systems have been introduced, moving from single distance (SD) to multi distances (MD) techniques, which are based on data collected at a single or multiple source-detector separations, respectively.