The CXC chemokines interleukin-8 and GRO/melanoma growth-stimulatory activity (GRO-alpha) are potent activators of neutrophils and lymphocytes, but also stimulate growth and differentiation of nonhematopoietic cells like keratinocytes, fibroblasts, and melanocytes. High mRNA and protein levels have been detected in psoriatic epidermis. Chemokine activation of target cells is mediated by specific receptors and two CXC receptors have been described with similar affinity for interleukin-8 but different affinities for GRO-alpha. In this study, we examined the expression of both CXCR1 and CXCR2 in psoriatic tissue, identifying the target cells of chemokine activation in psoriasis. By immunohistochemistry and in situ hybridization, as confirmed by northern blot analysis and reverse transcriptase polymerase chain reaction, we could detect expression of the CXCR2 in suprabasal lesional psoriatic keratinocytes but not in healthy skin. The CXCR1 could not be localized in psoriatic keratinocytes with immunohistochemistry and in situ hybridization, but infiltrating cells in the dermal compartment expressed both types of receptors. These data suggest that in addition to neutrophil activation by both CXCR1 and CXCR2, activation of keratinocytes mediated by CXCR2 could contribute to the characteristic epidermal changes observed in psoriasis.