The Athenian epidemic of 430-426 BC, at the outbreak of the Peloponnesian War, caused the death of the great statesman, Pericles, decimated the population and contributed significantly to the decline and fall of classical Greece. In his remarkable documentation of the epidemic, Thucydides (who survived the disease) not only left us a clear clinical picture of the pestilence but also identified its infectious nature and the fact that it conferred at least partial immunity on survivors. As confirmed by a large number of scholars who studied the subject, Thucydides' description does not accurately fit any existing disease, but we suggest that analysis of the signs and symptoms, considered in conjunction with significant epidemiological evidence, narrows down the many possibilities to epidemic typhus, plague, arboviral disease (e.g. Rift Valley fever) and smallpox. Typhus and smallpox fit best, but we favour the latter for reasons given. Unless further primary sources of information become available (and this seems most unlikely), productive speculation as to the cause of Thucydides' epidemic has probably reached the end of the road.