Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease. Recently, it was demonstrated that a large proportion of individuals with AD have an epidermal expression deficiency of filaggrin (FLG). This unique finding may have great implications for our understanding of nickel sensitization because nickel is chelated in the epidermis and perhaps to FLG. This review aims to briefly present the current knowledge about nickel sensitization in relation to FLG deficiency and speculate on its possible implications. The new knowledge concerning loss-of-function mutations in the FLG gene (the lack of specific nickel-chelating power in the stratum corneum and a generally defective skin barrier) suggests that an additive effect from irritants and nickel may aggravate hand eczema in individuals with loss-of-function mutations in the FLG gene. This hypothesis calls for a reevaluation of the potential risk of nickel sensitization through the establishment of cohorts with and without such mutations.