Sleep deprivation is an increasing problem in the modern age. While molecular theories on the mechanism of sleep are still developing, sleep’s importance for cognitive function and physical health has been well reported. In the past 2 decades, major advances in the genetics of sleep have been made. Among families of natural short sleepers averaging around 4-6 hours nightly, mutations on 4 genes (DEC2, ADRB1, NPSR1, and GRM1) have been associated with significantly shorter sleep without observed cognitive or health detriments. Studies in mice have further established causality of these mutations as well as finding increased resistance to neurodegeneration. Yet, despite these promising results, there is a current lack of studies investigating potential chronic risks of sleep deprivation, particularly physical and physiological effects that may not be apparent. For circadian repressor element DEC2, circadian dysregulation risks should be evaluated further. For adrenergic receptor ADRB1, cardiovascular and heart failure risks would be of interest. For NPSR1, asthma and other immune responses, as well as mood disorders are relevant. For the currently least studied G-protein receptor GRM1, its altered regulation of the extracellular signal-regulated kinase (ERK) pathway could result in developmental and proliferation effects. While these familial natural short sleep genes hold potential for our understanding of sleep and therapeutic development, it is critical not to overdraw conclusions. By investigating the possible downstream effects, one can be aware of the potential risks of natural short-sleep genetics, better understand the mechanisms of sleep, and advance research in reducing the harms of sleep deprivation.