Global climate change promotes warming temperatures and altered salinities that pose threats to aquatic ecosystems and species, such as Hyalella azteca. Moreover, these threats to aquatic ecosystems are exacerbated by agricultural, urban, and industrial pesticide runoff. In the state of California in 2012, pyrethroid insecticides were the seventh most applied group by licensed professional applicators for pest control and landscape maintenance. Some species, specifically H. azteca have developed non-target resistance to pyrethroids in California. It is imperative to understand whether the bioenergetic cost of resistance makes H. azteca more susceptible to warming and salinity effects in the presence of contaminants. This research presents an assessment on how multiple stressors can affect the toxicity of permethrin (pyrethroid insecticide) on one Wild-type and two pyrethroid- resistant species of H. azteca, belonging to different clades. A series of 96-h acute toxicity tests exposing animals to a concentration range of permethrin were performed with compounding stress from temperatures (18, 23 and 28 °C) and salinities (0.2, 1.0, and 6.0 practical salinity units [PSU]). Findings indicate resistant H. azteca cultured in pyrethroid-free settings have maintained resistance to permethrin over time, whereas the wild-type population did not develop any resistance over the course of experimentation. For resistant H. azteca, changes in salinity and temperature both increased and decreased survival of H. azteca exposed to permethrin. Between the two resistant clades, not only was survival affected, but the average slope of the dose-response curve was significantly different (p < 0.05); clade D was more susceptible to pyrethroids when coping with warming and higher salinity than clade C., Differential susceptibility potentially indicates that distinct resistance mutations confer a difference in the potency and mode of toxic action. The results provide insight to how changes posed by climate change, coupled with pyrethroid pesticides could be detrimental to this species, and conversely, how in some scenarios, changes to temperature and salinity might actually benefit the survival of H. azteca. These findings further indicate the importance of considering global climate change effects into risk assessments of emerging and legacy use contaminants.