Cellular senescence is a response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation and persistent DNA damage. In particular, radiation damage induces oxidative base damage and bond breaking in the DNA double-helix structure, which are treated by dedicated enzymatic repair pathways. In this review we discuss the correlation between senescence and the accumulation of non-repaired single-strand breaks, as it could occur during radiation therapy treatments. Recent experiments of cell irradiation in vitro by high-energy photons showed that single-strand breaks may be preferentially produced at the borders of the irradiated region, thereby inducing senescence, in competition with the apoptosis end-point typically induced by double-strand breaks. Such a peculiar response to radiation damage has been proposed as a possible source of radiation-induced second primary cancers, when such cells with accumulated, non-repaired single-strand breaks evade the senescent state at much later times. The peculiarities of strand-break repair pathways are highlighted, also in relation with the base-excision pathway that repairs several different DNA oxidation defects.