Pulpal and periapical diseases affect a large segment of the population. The role of microbial infections and host effector molecules in these diseases is well established. However, the interaction between host genes and environmental factors in disease susceptibility and progression is less well understood. Studies of genetic polymorphisms in disease relevant genes have suggested that individual predisposition may contribute to susceptibility to pulpal and periapical diseases. Other studies have explored the contribution of epigenetic mechanisms to these diseases. Ongoing research expands the spectrum of non-coding RNAs in pulpal disease to include viral microRNAs as well. This review summarizes recent advances in the genetic and epigenetic characterization of pulpal and periapical disease, with special emphasis on recent data that address the pathogenesis of irreversible pulpal pathosis and apical periodontitis. Specifically, proinflammatory and anti-inflammatory gene expression and gene polymorphism, as well as recent data on DNA methylation and microRNAs are reviewed. Improved understanding of these mechanisms may aid in disease prevention as well as in improved treatment outcomes.