Crayfish are benthic aquatic macroinvertebrates and are considered a keystone species because they play a pivotal role in the aquatic habitat, transferring energy within the aquatic food web and between the aquatic and terrestrial food chains. Additionally, crayfish are of great economical value as they are farmed in many parts of the world. In the wild, crayfish are found in ditches, streams, rivers and lakes bordering agricultural, industrial, mining and urban areas and are thus often exposed to contaminants. These contaminants (or xenobiotics) may enter into the aquatic environment through run-off, precipitation events and/or drainage. Crayfish can be used as a bioindicator species to measure contamination because they have low genetic and ecological variability, a large distribution, a long life-span, large body size, relatively low mobility and are easily reared in a laboratory setting. Further, crayfish exhibit measureable changes in population size, behavior, tissue accumulation, tissue histology and other physiological responses when exposed to contaminants. Given this, crayfish can be actively monitored in the field and laboratory, and may serve as a sentinel species when exposed to xenobiotics. In this chapter we present studies that use crayfish as a non-traditional model organism to study the effects of pharmaceuticals, agricultural chemicals and metals. We discuss lethality (i.e. 96 h LC₅₀ levels and population sizes) and non-lethal changes (e.g. accumulation, histological, behavioral and physiological changes) that occur in crayfish after exposure to sublethal concentrations of xenobiotics. We conclude that crayfish should be used more frequently as a bioindicator to assess contamination.