The US Environmental Protection Agency is developing a national water quality criterion for selenium that is based on concentrations of the element in fish tissue. Although this approach offers advantages over the current water-based regulations, it also presents new challenges with respect to implementation. A comprehensive protocol that answers the “what, where, and when” is essential with the new tissue-based approach in order to ensure proper acquisition of data that apply to the criterion. Dischargers will need to understand selenium transport, cycling, and bioaccumulation in order to effectively monitor for the criterion and, if necessary, develop site-specific standards. This paper discusses 11 key issues that affect the implementation of a tissue-based criterion, ranging from the selection of fish species to the importance of hydrological units in the sampling design. It also outlines a strategy that incorporates both water column and tissue-based approaches. A national generic safety-net water criterion could be combined with a fish tissue–based criterion for site-specific implementation. For the majority of waters nationwide, National Pollution Discharge Elimination System permitting and other activities associated with the Clean Water Act could continue without the increased expense of sampling and interpreting biological materials. Dischargers would do biotic sampling intermittently (not a routine monitoring burden) on fish tissue relative to the fish tissue criterion. Only when the fish tissue criterion is exceeded would a full site-specific analysis including development of intermedia translation factors be necessary.