Fish are important dietary items that provide essential nutrients. Fish however, bioaccumulate monomethyl mercury (MMHg) and organo-halogenated pollutants (OHP) that are persistent bioaccumulative and toxic substances (PBTS). Unlike man-made OHP, MMHg is mainly of natural origin but background concentrations of aquatic systems are determined by the environmental Hg-methylating potential. Industrial activities can modulate environmental discharges and fish bioaccumulation of PBTS. Fish and seafood consumption are associated with human body load of PBTS, but farming practices that utilize fishmeal increase the terrestrial food chain resulting in farm-animal accumulation of PBTS. These substances are neurotoxic and endocrine active that can impact humans and wild life, but chemical characteristics of MMHg and OHP modulate interactions with animal tissues. MMHg is protein reactive with a faster metabolism (months) than OHP that are stored and slowly (years) metabolized in fat tissues. Except for brain-Hg, neither Hg nor OHP in tissues are markers of toxic effects; however, deficits in neurobehavioral test-scores of children have been shown in some fish-eating populations. These deficits are transient and within normal range, and are not prodromes of neurological diseases. Although population studies show that consumption of fish at current levels of contamination do not explain neurological disorders, endocrine activity remains controversial. Understanding risk of hazard caused by fish-PBTS consumption requires a wide range of expertise. We discuss chemical, toxic, metabolic, and ecological characteristics associated with PBTS in fish. There are proven health outcome derived from fish consumption, while risk of exposure to avoidable PBTS is a chance that can be minimized by societal actions.