This paper documents the emergent snake ‘fishery’ occurring on Tonle Sap Lake where an estimated 6.9 million snakes (mostly homalopsids) are removed annually, representing the world’s largest exploitation of a single snake assemblage. Based on interviews with hunters, we found that snake catches declined by 74–84% between 2000 and 2005, raising strong concerns about the sustainability of this hunting operation. A combination of experimental trials to estimate population sizes and extensive catch and trade monitoring programs indicated that population density varies both spatially and temporally, largely due to the seasonally fluctuating environment of Tonle Sap Lake. The quantity of snakes captured mirrors the lake’s seasonal fluctuations, due to temporal changes in both catch per unit effort and the number of people hunting. Through interviews with hunters we scored the seven exploited species for perceived changes in catch size. All species were reported as declining and their scores match their predicted vulnerability based on a combination of timing of exploitation relative to breeding, proportion of catch consisting of mature females and large fecund females, fecundity, body size, size at maturity, and vulnerability to capture by gill nets. This information can inform conservation decisions for the longterm preservation of this snake assemblage. We propose emphasis should be placed on the snake skin trade that is targeting the largest, highly fecund females, and that any efforts to reduce hunting should focus on the peak in trade that occurs during the main breeding season.