In recent years, the role of “sleepiness at the wheel” in the occurrence of accidents has been increasingly highlighted with several national and international public health campaigns based on consensual research publications. However, one aspect of this phenomenon is rarely taken into account, i.e., the risk of sleep-induced accidents while riding powered two-wheelers (PTWs). PTWs are indeed involved in a high percentage of fatal accidents mostly with young male riders. The effects of sleepiness may be different in drivers and riders, partly because riders may be stimulated more by the road environment. But riders (differently from drivers) have also to maintain continuously a balance between their own stability and the need of following the road, even when they are directly exposed to adverse climatic conditions. We, therefore, gathered the limited scientific literature on this topic and tried to analyze how riders may be affected differently by sleepiness. Finally we provide some suggestions as to how this question may be better approached in the future.