Sleep disorders and various common acute and chronic medical conditions directly or indirectly affect the quality and quantity of one’s sleep or otherwise cause excessive daytime fatigue. This article reviews the potential contribution of several prevalent medical conditions – allergic rhinitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis/osteoarthritis – and chronic fatigue syndrome and clinical sleep disorders – insomnia, obstructive sleep apnea, narcolepsy, periodic limb movement of sleep, and restless legs syndrome – to the risk for drowsy-driving road crashes. It also explores the literature on the cost-benefit of preventive interventions, using obstructive sleep apnea as an example. Although numerous investigations have addressed the impact of sleep and medical disorders on quality of life, few have specifically addressed their potential deleterious effect on driving performance and road incidents. Moreover, since past studies have focused on the survivors of driver crashes, they may be biased. Representative population-based prospective multidisciplinary studies are urgently required to clarify the role of the fatigue associated with common ailments and medications on traffic crash risk of both commercial and non-commercial drivers and to comprehensively assess the cost-effectiveness of intervention strategies.