High rates of mortality have been reported in coho salmon (Oncorhynchus kisutch) entering urban rivers in Seattle, Washington. The behavioral symptoms preceding mortality include erratic swimming, gasping, and loss of equilibrium. Through laboratory testing, it has been confirmed that 6PPD-quinone (6PPD-Q), the transformation product of the tire anti-degradant, 6PPD, is capable of causing the same effect at low doses. The precise adverse outcome pathway (AOP) leading to 6PPD-Q-induced mortality is still not fully understood, however, cardiorespiratory function appears to be affected. Increased vascular permeability, hematological effects, and mitochondrial impairment coincide with mortality. The potency of 6PPD-Q differs substantially between fish species (even those that are phylogenetically similar), with some salmonids demonstrating relatively high tolerance to the chemical in comparison to coho salmon. Dissimilar responses between subpopulations of the same species (e.g., westslope cutthroat trout and coastal cutthroat trout) have also been reported. Thus, specific inter- and intraspecies genetic variations may offer clues about the molecular underpinnings of 6PPD-Q-induced mortality. Tolerant fish species tend to exhibit higher levels of hydroxylated metabolites when exposed to 6PPD-Q, but no specific biotransformation enzyme has been implicated. Determination of the molecular initiating event(s) and/or early key event(s) in the AOP leading to 6PPD-Q-induced mortality could significantly accelerate the search for a suitable alternative chemical and could help researchers screen for additional potentially sensitive species to inform better targeted mitigation strategies. Here, we assemble the current body-of-evidence on 6PPD-Q toxicity in fish, including both sub-lethal and apical endpoints, using a matrix-style approach with relevant parameters such as effect concentration, species, life stage, test duration, and study quality. We present the priority evidence holistically and identify potential AOPs that warrant further investigation.