A series of modeling simulations was performed to evaluate the underlying factors and principles that drive the uncertainty in measured bioaccumulation factors (BAFs) and biota-sediment accumulation factors (BSAFs) for fish, and to determine which sampling designs minimize those uncertainties. Temporal variability of chemical concentrations in the water column, and the metabolism rate and n-octanol-water partition coefficient (Kow) for the chemical were determined to be the dominant factors that influenced the field-sampling design. Spatial variability of the chemical concentrations, food web structure, and the sediment-water column concentration quotient had a lesser importance upon the overall design. The simulations also demonstrated that collection of composite water samples in comparison to grab water samples resulted in reductions in the uncertainties associated with measured BAFs. Some illustrative sampling design structures for BAF and BSAF measurements based upon the temporal variability of chemical concentrations in the water column and the metabolism rate and Kow for the chemical were developed. These illustrative designs provided a sense of how sampling design structures, that is, the number and spacing over time of sampling events, might be influenced by differences in temporal variabilities, metabolism rates, and Kow. Although the importance of spatial variability was discounted as a major factor in the design process, sampling of water and sediment across the immediate home range of the sampled organism is required for successful measurements because poor spatial coordination of organism, water, or sediment samples will yield BAFs and BSAFs with large and unknown biases.