Between 1906 and 1909 the biologist Ronald Ross and the classicist W.H.S. Jones pioneered interdisciplinary research in biology and history in advancing the claim that malaria had been crucial in the decline of golden-age Greece (fourth century BCE). The idea had originated with Ross, winner of the Nobel Prize for demonstrating the importance of mosquitoes in the spread of the disease. Jones assembled what, today, we would call an interdisciplinary network of collaborators in the sciences and humanities. But early negative reviews of Jones's "Malaria and Greek History" (1909) by classicists and historians ended the project, despite a positive reception among malariologists. Today, the "Jones hypothesis" is often used to exemplify the naïvete of past scholarship, and few examine Jones's evidence and reasoning. In this age of renewed interdisciplinarity, a review of what went wrong is timely. Jones and Ross knew they were opening new methodological territory and struggled with the challenges of multiple ways of knowing. Over 100 years later, malaria remains an important site of historical-biological research, yet integration is elusive. After reviewing the Jones-Ross relationship, Jones's interdisciplinary campaign, and the reception of the hypothesis among classicists/ancient historians and in malariology, we conclude by highlighting some of the specific challenges faced by those exploring the interface of biology and history.