Sudden unexpected death in infancy (SUDI) is an umbrella label that some employ to encompass all sudden unexpected infant deaths, whether or not explained, while others restrict its use to cases in which the cause of death is uncertain, but possibly due to asphyxia as may occur, for example, with sleeping prone, face down on a soft sleep surface, and/or being found with the head covered. Since sudden infant death syndrome (SIDS) is a diagnosis of exclusion, there is an inevitable interface between it and those cases whose deaths are potentially caused by unsafe sleep environments. This interface is especially blurred given the lack of definitive, easily identifiable postmortem marker(s) for SIDS. Therefore, present SIDS definitions are imprecise and its diagnosis remains one of exclusion. Improved death scene investigation has resulted in a diagnostic shift away from SIDS towards other causes of death such as positional asphyxia or undetermined. Unfortunately incomplete death scene investigation has hampered evaluation of the real circumstances of death in too many of the cases further contributing to confusion. In this report, the purposes for and primary definitions of SIDS are delineated. Subsequent discussion focuses on the increasing challenge to incorporate risk factors and the underlying pathology germane to the pathophysiology of SIDS into future definitions. This challenge is matched by the need to develop affordable and widely available testing that will identify pathology relevant to medical examiners and others charged with certifying the cause and manner of death.