Mandated efforts to assess chemicals for their potential to bioaccumulate within the environment are increasingly moving into the realm of data inadequacy. Consequently, there is an increasing reliance on predictive tools to complete regulatory requirements in a timely and cost-effective manner. The kinetic processes of absorption, distribution, metabolism, and elimination (ADME) determine the extent to which chemicals accumulate in fish and other biota. Current mathematical models of bioaccumulation implicitly or explicitly consider these ADME processes, but there is a lack of data needed to specify critical model input parameters. This is particularly true for compounds that are metabolized, exhibit restricted diffusion across biological membranes, or do not partition simply to tissue lipid. Here we discuss the potential of in vitro test systems to provide needed data for bioaccumulation modeling efforts. Recent studies demonstrate the utility of these systems and provide a “proof of concept” for the prediction models. Computational methods that predict ADME processes from an evaluation of chemical structure are also described. Most regulatory agencies perform bioaccumulation assessments using a weight-of-evidence approach. A strategy is presented for incorporating predictive methods into this approach. To implement this strategy it is important to understand the “domain of applicability” of both in vitro and structure-based approaches, and the context in which they are applied.