Oxygen free radicals have a major impact on senescence of primary human cells. In replicative senescence, which is induced by uncapping of telomeres, the rate of telomere shortening is largely determined by telomere-specific accumulation of DNA damage induced by reactive oxygen species (ROS). More intense ROS-generating stressors can induce premature senescence via generation of telomere-independent DNA damage. Interestingly, ROS levels were also elevated when premature senescence was triggered by pathways downstream or independent of DNA damage. This has led to the suggestion that ROS generation could be a specific component of the signalling pathways inducing senescence. However, the available data are compatible with the concept that senescence is triggered as a DNA damage response. ROS appear to be involved as inducers of DNA damage rather than as specific signalling molecules. The upregulation of ROS production often seen in premature senescence might be related to retrograde response initiated by mitochondria.