We present evidence from a variety of physical and biological proxies for a severe drought that affected the mid-continent of North America between 4.1 and 4.3 ka. Rapid climate changes associated with the event had large and widespread ecological effects, including dune reactivation, forest fires and long-term changes in forest composition, highlighting a clear ecological vulnerability to similar future changes. Drought is also documented in the Middle East and portions of Africa and Asia, where it was similar in timing, duration and magnitude to that recorded in the central North American records. Some regions at high latitudes, including northern Europe and Siberia, experienced cooler and/or wetter conditions. Widespread mid-latitude and subtropical drought, associated with increased moisture at some high latitudes, has been linked in the instrumental record to an unusually steep sea surface temperature (SST) gradient between the tropical eastern and western Pacific Ocean (La Ninia) and increased warmth in other equatorial oceans. Similar SST patterns may have occurred at 4.2 ka, possibly associated with external forcing or amplification of these spatial modes by variations in solar irradiance or volcanism. However, changes in SST distribution bracketing the 4.2 ka event are poorly known in most regions and data are insufficient to estimate magnitude of changes in solar and volcanic forcing at this time. Further research is needed to delineate geographical patterns of moisture changes, ecological responses, possible forcing mechanisms and climatology of this severe climatic event.