Irritant contact dermatitis (ICD) is the most common form of contact dermatitis. ICD does not represent a single monomorphic entity, but rather a complex biologic syndrome with diverse pathophysiology and clinical manifestations. ICD represents an innate immune response of the skin to direct injury that arises when irritating stimuli overpower the skin’s defense and repair capabilities. Irritants are recognized as “danger signals” by the innate immune system and generate inflammatory responses by similar pathways than those used by pathogens, ultraviolet radiation, or mechanical trauma. The mechanism of ICD involves three main steps: disruption of the skin barrier, activation of the epidermal cells, and cytokine/chemokine release, leading to the stimulation of the innate immune system, inflammation, and skin damage. Early events in the elicitation of acute or chronic ICD include the release of pro-inflammatory mediators such as interleukin (IL)-1α, IL-1β, and tumor necrosis factor alpha (TNF-α) from keratinocytes as a consequence of perturbation of skin barrier, regardless of whether it is chemically or mechanically induced. These events are followed by the secretion of IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF), recruiting immune cells to the injured skin and inducing their proliferation. Induction of cell adhesion molecules such as ICAM-1 on the keratinocytes and E-selectin on the endothelial cells facilitates the extravasation of inflammatory T lymphocytes to the skin. The immune cascade is then activated independently of the antigen presentation pathway, by direct recruitment and activation of T lymphocytes without the induction of antigen-specific effector and memory T cells. There have been a number of advances in the understanding of ICD, and some interesting new areas of research include the role of the loss-of-function mutations in the gene encoding filaggrin and the TNF-α gene polymorphisms. Further understanding of the molecular pathways in contact dermatitis would provide the basis for newer, more targeted treatment options.