Ruffe were introduced into Duluth Harbor, Minnesota in the early 1980s, probably by release of ballast water from sea-going freighters. Since then, it has become the most abundant species in the fish community. The sensitivity of ruffe to a number of piscicides has been demonstrated, however, the feasibility of using piscicides to control populations depends on whether ruffe can detect piscicides and move to untreated water. We used a two-choice preference testing system to evaluate avoidance or attraction reactions of ruffe during exposures to the lampricides TFM and bayluscide and the general fish toxicants rotenone and antimycin. We used a second testing system to evaluate the potential for benthic ruffe to move vertically in the water column to avoid piscicides dissolving from experimental bottom-release formulations of bayluscide and antimycin. Near-lethal concentrations of TFM and rotenone tended to repel ruffe. Antimycin and bayluscide did not seem to repel ruffe in the avoidance chamber, but bottom-release formulations (antimycin granules—0.25% a.i. and bayluscide granules—3.2% a.i.) did cause increased swimming and surfacing activity among ruffe in column tests. We conclude that TFM and rotenone could be used to treat entire bodies of water, while bottom-release formulations of antimycin and bayluscide may have more application for treating localized concentrations of ruffe.