The allergic diseases comprise a group of chronic inflammatory conditions that display a broad spectrum of clinical manifestations primarily mediated by immunoglobulin E (IgE). The prevalence and severity of these IgE-mediated allergic disorders have increased dramatically over the past few decades and are becoming a global health problem. Although genetics plays an important role in determining who develops these atopic disorders, genetics alone cannot fully explain this rapid growth. Results of numerous studies have indicated that epigenetics plays a major pathogenetic role by superimposing its effects above the DNA primal genetic molecule through interactions with and between various susceptibility genes, immunologic influences, and environmental factors. In this article, the importance and relationships of genetics and epigenetics to an understanding of the immune system in health and in disease were reviewed together with the principles and mechanisms that underlie these entities and which relate to clinical allergy practice. A specific focus of the article was directed to the recent recognition that the IgE-driven atopic disorders are driven by aberrant immune responses in which CD25 Forkhead box P3 (FoxP3) T-regulatory (Treg) cells that normally suppress inflammatory events are often poorly functioning. Based on our previous published findings that methylated DNA CpG (cytosine [C], phosphate [p], guanine [G]) oligonucleotide (ODN) but not unmethylated CpG ODN sequence was shown to promote FoxP3 expression in human CD4 T cells, the article reviewed the application of DNA methylation and Treg induction to cancer, autoimmune diseases, and the allergic disorders. The central unifying theme of DNA methylation epigenetic mechanism is its comparative description to an electronic "switch," which, when in the methylated state functions in the "closed" position with gene silencing, genome stability, and decreased gene expression, whereas DNA hypomethylation is analogous to the "opened" position of the switch, which leads to active transcription and increased gene expression. Of the three epigenetic mechanisms that include DNA methylation, covalent posttranslational histone modifications, and micro-RNA-mediated gene silencing, DNA methylation plays the major role in understanding mechanisms involved in allergy and immunotherapy. Epigenetics holds the key to unraveling the complex associations between disease phenotypes and endotypes, identifying safer and effective therapies, and creating a better diagnosis and treatment of allergic diseases. Genetics loads the gun and epigenetics pulls the trigger.