Contact sensitization is the initial process involved in the development of an allergic reaction to xenobiotic environmental substances. Here, we briefly describe the differences between irritant and allergic contact dermatitis. Then, we highlight the essential steps involved in the development of an ACD reaction, i.e., the protein binding of haptens, genetic factors influencing the penetration of sensitizers into the skin, the different mechanisms driving the initial development of an inflammatory cytokine micromilieu enabling the full maturation of dendritic cells, the role of pre- and pro-haptens, antigen presentation and T cell activation via MHC and CD1 molecules, dendritic cell (DC) migration, and potential LC contribution as well as the different T cell subsets involved in ACD. In addition, we discuss the latest publications regarding factors that might influence the sensitizing potential such as repeated sensitizer application, penetration enhancers, humidity of the skin, microbiota, Tregs, and phthalates. Last but not least, we briefly touch upon novel targets for drug development that might serve as treatment options for ACD.