Background: Hereditary gingival fibromatosis (HGF) is a rare condition characterized by slowly progressive overgrowth of the gingiva. The severity of overgrowth may differ from mild causing phonetic and masticatory issues, to severe resulting in diastemas or malposition of teeth. Both, autosomal-dominant and autosomal-recessive forms of HGF are described. The aim of this review is a clinical overview, as well as a summary and discussion of the involvement of candidate chromosomal regions, pathogenic variants of genes, and candidate genes in the pathogenesis of HGF. The loci related to non-syndromic HGF have been identified on chromosome 2 (GINGF, GINGF3), chromosome 5 (GINGF2), chromosome 11 (GINGF4), and 4 (GINGF5). Of these loci, pathogenic variants of the SOS-1 and REST genes inducing HGF have been identified in the GINGF and the GINGF5, respectively. Furthermore, among the top 10 clusters of genes ranked by enrichment score, ATP binding, and fibronectin encoding genes were proposed as related to HGF. Conclusion: The analysis of clinical reports as well as translational genetic studies published since the late’90s indicate the clinical and genetic heterogeneity of non-syndromic HGF and point out the importance of genetic studies and bioinformatics of more numerous unrelated families to identify novel pathogenic variants potentially inducing HGF. This strategy will help to unravel the molecular mechanisms as well as uncover specific targets for novel and less invasive therapies of this rare, orphan condition.