Ultraviolet (UV) radiation in sunlight is the major environmental cause of skin cancer. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a proven critical tumor suppressor. We report here that UVB downregulates PTEN in primary human keratinocytes, human HaCaT keratinocytes and mouse skin. As compared with normal skin, PTEN levels are reduced in human actinic keratosis, a precancerous skin lesion caused by solar UV. PTEN downregulation is mediated by two mechanisms: (1) PTEN is cleaved by active caspase in apoptotic cells in which AKT activation is reduced; and (2) PTEN transcription is suppressed in surviving cells, and this suppression is independent of caspase activation and occurs in parallel with increased ERK and AKT activation. We report here that the combination of ERK and AKT activation is crucial for PTEN suppression in surviving cells following UVB irradiation. AKT activation is higher in UVB-irradiated surviving cells as compared with unirradiated cells. The ERK and AKT pathways are involved in sustaining PTEN suppression in UVB-exposed cells. Increasing PTEN expression enhances apoptosis of keratinocytes in response to UVB irradiation. Our findings indicate that (1) UVB radiation suppresses PTEN expression in keratinocytes; and (2) the ERK/AKT/PTEN axis may form a positive feedback loop following UVB irradiation. Our identification of PTEN as a critical molecular target of UVB provides new insights into the pathogenesis of skin cancer.