Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited disorders, characterized by death of the retinal photoreceptor cells, leading to progressive visual impairment. One form of RP is caused by mutations in the ubiquitously expressed splicing factor, PRPF31, this form being known as RP11. An intriguing feature of RP11 is the presence of non-penetrance, which has been observed in the majority of PRPF31 mutation-carrying families. In contrast to variable expressivity, which is highly pervasive, true non-penetrance is a very rare phenomenon in Mendelian disorders. In this article, the molecular mechanisms underlying phenotypic non-penetrance in RP11 are explored. It is an elegant example of how our understanding of monogenic disorders has evolved from studying only the disease gene, to considering a mutation on the genetic background of the individual - the logical evolution in this genomic era.