Diffuse Optical Spectroscopy (DOS) is a noninvasive technology that uses near-infrared (NIR) light (600-1100 nm) to investigate human tissue. Implementations of the technology materialize in diverse areas of medicine, including pulse oximetry for measuring tissue oxygen saturation, functional Near Infrared Spectroscopy (fNIRS) for studying brain activity, and Diffuse Optical Tomography (DOT) for safely monitoring how tumors respond to chemotherapy.Frequency Domain (FD) DOS builds on simpler attenuation-based techniques by introducing modulation (0 - 1000 MHz) to the light source amplitude. This enables quantitative recovery of both absorption and scattering in the tissue simultaneously via measurements of attenuation and phase shift in the intensity-modulated signal. Hybrid broadband DOS extends the measurement of FD-DOS optical properties, from several discrete wavelengths to a continuous band across the NIR region, to obtain broadband absorption and scattering spectra.In this work, we examine several approaches aimed at improving the performance and application of FD-DOS based imaging. First, we apply hybrid broadband DOS with the goal of inferring the presence of malaria parasites in infected individuals through the sensitive detection of a minor tissue absorber called hemozoin. We follow up with an in-depth study of the accuracy and precision of frequency domain DOS, with an eye toward achieving the best measurements possible with current instruments. Lastly, we evaluate a new technique called Structured Interrogation, which is based on the use of multiple in-phase modulated optical sources, to improve 3D localization and characterization of tissue heterogeneities.