Some chemicals act as human carcinogens in various organ systems including the skin. Mice have been an ideal model to study a wide variety of chemical carcinogens because the pathogenesis in that species often mirrors that in humans. However, different mouse strains vary in their susceptibility to these agents. Thus, reliance on a single strain may lead to inaccurate findings. 2-Ethylhexyl acrylate (2-EHA) is an acrylate used as a co-monomer in the production of polymer resins for adhesives, latex paints, cross-linking agents, finishes for textiles and leather, and paper coatings. Monomer exposure may occur in occupational settings where it is produced or used; the only exposure that may occur to consumers or construction personnel is trace amounts in the final polymer product. There are no reports of cancer in humans caused by exposure to 2-EHA. However, 2-EHA has been reported to cause cancer in one strain of mice. This is an important issue since recommendations about its safety in humans depend, in part, on information derived from animal studies. We reviewed the literature on the preclinical effects of acrylates on skin carcinogenesis in C3H/HeJ mice, which can be criticized because of peculiarities in the immunological composition of that strain, the lack of rigorous histopathologic characterization of tumors that developed, the high doses of 2-EHA that were used for evaluation, and the lack of reproducibility in a second strain of mice. The C3H/HeJ mouse model is not ideal as it has a mutation in Toll-like receptor 4 (TLR4) that impairs its innate and adaptive immune responses. Inconsistencies in the histological evaluation of tumors induced in C3H/HeJ mice provide further evidence that the tumorigenic effect of 2-EHA was strain specific, a result of chronic inflammation during the promotion stage and/or a skewed immune response caused by the TLR4 mutation. In conclusion, 2-EHA has not convincingly been demonstrated to have skin carcinogenic activity to date. More relevant mouse models that mimic human squamous cell carcinoma, basal cell carcinoma, and melanoma with amounts that do not exceed a maximum tolerated dose are needed to assess the carcinogenic effects of 2-EHA.