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Metal nanoparticles have recently been demonstrated as combined targeting and therapeutic agents in cancer management. Efforts to design protocols for an effective in vivo therapeutic outcome rely on the knowledge of the nanoparticle localization and concentration; however, a non-invasive in vivo method to determine gold nanoparticle concentration in tissue does not currently exist. In the recent years optical methods are widely being explored as a non-invasive tool for diagnostic and therapeutic applications for various disease conditions. Among various optical techniques, diffuse optical spectroscopy (DOS) is used to quantitatively measure tissue constituents (oxygen saturation, Hb concentration, scattering) in vivo. Hence, the present study was aimed to demonstrate the use of DOS for the non-invasive measurement of nanoparticle concentrations using an inverse algorithm. Preliminary studies were performed on tissue simulating phantoms fabricated from polystyrene beads, intralipid, and hemoglobin. Gold nanoshells at varying concentrations (1.027×10⁸ to 15.40×10⁸ particles/ml) were added to the phantom and the diffuse optical spectra were measured using a fiber optic probe. The gold nanoshell concentration in the tissue-simulating phantom was estimated using the inverse algorithm. In vivo studies were performed on mouse xenograft tumor model. Six to eight weeks old nude mice (n=11) were subcutaneously injected with c6-glioma (rat brain tumor) cells (1×10⁶ cells/injection) in the right flank and the animals were monitored for tumor growth, and they were used for the experiments when the tumor diameter reached approximately 1 cm diameter. Baseline DOS measurements were taken from the tumor spots of all the animals prior to the injection (tail vein) of nanoshells (8x10⁸ nanoshells/g), and the subsequent DOS were measured at 10 s, 1 hr and 24 hr postinjection times. The concentration of nanoshells was estimated as in tissue phantoms. The estimated nanoshell concentrations were correlated with neutron activation analysis (NAA) of the tissue samples extracted at the time points mentioned above. Tissue phantom measurements demonstrated the ability of DOS to extract nanoshell concentrations within the physiologically relevant range. In vivo measurements demonstrated the sensitivity of DOS to detect nanoshell present within the tumor at each of the time points, and these results were confirmed with NAA. These experiments demonstrate the feasibility of DOS to measure gold nanoshell concentrations in vivo. DOS may allow for longitudinal monitoring of gold nanoparticles in in vivo dosimetry and biodistribution studies.