The incomplete prediction of clinical phenotype from genotype in monogenic disorders assumes other complex mechanisms are responsible. Recent examples derived from well-known human diseases will be discussed in this review in the context of the roles of modifier genes, digenic and triallelic inheritance, and the consequence of imprinting and opposite transcripts in known human genetic disorders. Specifically, this review will focus on cystic fibrosis, Huntington's disease, sensory neural deafness due to Connexin gene mutations, Bardet-Biedl syndrome, and the Beckwith-Wiedemann syndrome as there is evidence that complex inheritance is responsible for at least part of the phenotypic variability that is not explainable by the genotype alone. This review is meant to extend and complement the other topics in this issue as the concept of atypical inheritance is explored in more detail.