Irritant contact dermatitis belongs within a spectrum of eczematous inflammatory skin conditions along with atopic and allergic contact dermatitis. Since the histopathological picture of all eczemas is basically identical they cannot be distinguished accurately based on morphology. Therefore, the main value of the skin biopsy is in terms of differential diagnosis. Most of the time irritant contact dermatitis will be easily distinguished histologically from non-eczematous conditions. Problems may arise in cases of psoriasis with higher degree of spongiosis or in overlapping cases between the two conditions. Also, the differentiation between palmoplantar psoriasis, chronic hand dermatitis, and hyperkeratotic hand eczema may be challenging. This diagnostic dilemma can be overcome in some cases with the aid of immunohistochemistry. Overexpression of IL-36 and beta defensin-2 is usually seen in cases of psoriasis but not in those of eczema. There still remains a certain percentage of cases in which an accurate diagnosis can’t be established because the diseases overlap both clinically and histologically.