Posterior open bite (POB) is one of the most severe malocclusions that can impair patients' masticatory functions, yet it is also a condition that is poorly understood and not well studied. Most reported cases are either sporadic or idiosyncratic with a diverse yet poorly understood etiology. Although primary failure of eruption (PFE), lateral tongue thrust, and certain medical syndromes or pathology of the temporomandibular joints have all been shown to cause POB, the complex interplay of environmental and genetic factors makes its etiopathogenesis a difficult subject to understand and investigate. Here, we provide a comprehensive review of the etiology of posterior open bite. Additionally, a genetic cause for POB is proposed through a report of an apparently non-syndromic familial case series with high POB penetrance across two generations. Further investigations of the gene(s) and mechanism(s) involved can not only provide a unique opportunity to better understand POB and the intricate muscular-occlusal relationship, but also offer powerful insight into the most effective approaches to clinical management of these (and potentially other) malocclusions.