This article provides a context to, attempts an explanation for, and proposes a response to the recent demonstration of rapid and severe decline of the native mammal fauna of Kakadu National Park. This decline is consistent with, but might be more accentuated than, declines reported elsewhere in northern Australia; however, such a comparison is constrained by the sparse information base across this region. Disconcertingly, the decline has similarities with the earlier phase of mammal extinctions that occurred elsewhere in Australia. We considered four proximate factors (individually or interactively) that might be driving the observed decline: habitat change, predation (by feral cats), poisoning (by invading cane toads), and novel disease. No single factor readily explains the current decline. The current rapid decline of mammals in Kakadu National Park and northern Australia suggests that the fate of biodiversity globally might be even bleaker than evident in recent reviews, and that the establishment of conservation reserves alone is insufficient to maintain biodiversity. This latter conclusion is not new; but the results reported here further stress the need to manage reserves far more intensively, purposefully, and effectively, and to audit regularly their biodiversity conservation performance.