Skin is the most frequent target of adverse drug reactions. These cutaneous drug reactions (CDRs) show varied clinical manifestations ranging from mildly discomforting rashes to life-threatening Stevens-Johnson syndrome or toxic epidermal necrolysis. Most CDRs appear to be immune mediated, although the mechanism by which they are initiated remains unclear. In this review, current knowledge of the mechanisms by which xenobiotics provoke immune responses in the skin after epicutaneous administration and how similar reactions may occur after systemic routes are summarised. This review also discusses a variety of genetic or environmental factors that may determine the susceptibility of individuals towards immune responses in skin following drug exposure.