Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX₃CL1 (fractalkine) and its unique receptor, CX₃CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX₃CR1-deficient mice and upon blocking CX₃CL1–CX₃CR1 interactions in wild-type mice. CX₃CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX₃CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX₃CL1 and CX₃CR1 regulate the pathology by controlling effector CD4⁺ T cell survival within inflamed tissues, adoptive transfer experiments established CX₃CR1 as a key regulator of CD4⁺ T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX₃CR1 and CX₃CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.