Diagnosing the cause of a species’ decline is one of the most challenging tasks faced by conservation practitioners. For a species approaching extinction, it is not possible to go back in time to measure the agents that operated at various stages of the decline. Accordingly, managers are often restricted to measuring factors currently affecting residual populations, which may not be related to factors that operated earlier in the decline, and inferring other mechanisms from different lines of evidence. In this review, I adopt a methodical diagnostic framework to comprehensively evaluate the potential causal factors for the decline of the eastern quoll (Dasyurus viverrinus) in Tasmania, and propose a hypothesis as to the cause of decline. Potential causal agents were gleaned from two key sources: factors implicated in the eastern quoll’s historical demise on the Australian mainland, and factors that changed during the recent period of quoll decline in Tasmania. The three most likely candidate causal agents were investigated over 4 years to evaluate their likely contribution to the decline. Here, I synthesise the findings from this recent research to advance a hypothesis as to the cause of the eastern quoll decline in Tasmania. I suggest that a period of unsuitable weather reduced quoll populations to an unprecedented low abundance, and that populations are now too small to overcome established threat intensities to which they were robust when at higher densities. Residual small populations are inherently more susceptible to demographic, environmental and genetic stochasticity and are unlikely to recover without management intervention. I propose a study design to experimentally test this hypothesis, and outline priority areas for future research and actions to guide in the future management and conservation of the species. This case study illustrates an approach by which practical species conservation problems might be solved and recovery strategies may be better informed, thereby ensuring positive conservation outcomes for threatened species.