Body composition assessment has been used to evaluate clinical interventions in research trials, and has the potential to improve patient care in the clinical setting. Body cell mass (BCM) is an important indicator of nutrition status; however, its measurement in the clinic has been limited. BCM can be estimated by the measurement of intracellular water (ICW). The assessment of extracellular water (ECW) is also important because many clinical populations undergo alterations in fluid distribution, particularly individuals with wasting, those receiving dialysis, and obese individuals. Bioimpedance spectroscopy (BIS) is a unique bioimpedance approach that differs in underlying basis from the more readily recognized single-frequency bioelectrical impedance analysis (SF-BIA) in that it does not require the use of statistically derived, population-specific prediction equations. It has the potential advantage of not only measuring total body water (TBW), as does SF-BIA, but also offering the unique capacity to differentiate between ECW and ICW and, thus, to provide an estimate of BCM. This literature review was conducted to compare available BIS devices to multiple dilution for measuring fluid compartments or BCM in a number of populations. Variable results regarding the ability of BIS to measure absolute volumes, as well as the observation of wide limits of variation, make BIS problematic for individual assessment in the clinic, particularly in populations with abnormal fluid distribution or body geometry. BIS has been found to be more accurate for measuring changes in fluid volumes or BCM, particularly in post-surgical and human immunodeficiency virus (HIV)-infected individuals. It is certainly possible that population-specific adjustments may improve the accuracy of BIS for assessing individuals in the clinical setting; however, additional research and development is needed before the method can be accepted for routine clinical use.