Differences in sampling and laboratory protocols, differences in techniques used to evaluate metrics, and differing scales of calibration and application prohibit the use of many existing multimetric indices (MMIs) in large-scale bioassessments. We describe an approach to developing MMIs of ecological condition that is applicable to a variety of biological assemblage types and to spatially extensive (regional, national) aquatic resource surveys. The process involves testing the performance characteristics of candidate metrics in several categories that correspond to key dimensions of biotic condition. The performance characteristics include: information content (range), reproducibility, calibration for natural gradients, responsiveness to stressor gradients, and independence from other metrics. The best-performing metric from each category is included in the final MMI. The consistency of the process enables development of separate MMIs in different regions that can be combined in a national assessment and that are more comparable across regions and taxonomic groups than a set of independently developed MMIs would be. We provide an example of the process applied to macroinvertebrate data from the US Environmental Protection Agency's Wadeable Streams Assessment (WSA) from 3045 sites (of which 1390 were WSA probability sites). The MMIs developed for the WSA demonstrate the feasibility of conducting bioassessments at continental scales and provide a basis for interpreting existing MMIs from regional- and national-level perspectives.