Besides its role in healing and regeneration, senescence is linked to aging and the occurrence of age-related pathologies. To develop immunotherapies aiming to eliminate senescent cells in a pathological context, it is important to identify targets that are highly specific to these senescent cells. Herein, we combine Omics and cell-based approaches to define cell surface senescence markers that can be targeted via immunotherapy. We started by developing and dissecting a genotoxic stress-induced premature senescence model of human fibroblasts in vitro. After the complete characterization of its senescent phenotype, we investigated the expression of potential senescence markers in this model. Interestingly, using Omics approaches, we identified novel cell surface markers that are exclusively expressed in senescent cells, which makes them of interest for immunotherapies. In addition, whereas some senescence markers were upregulated at early and late senescence states, others were downregulated, emphasizing the role of the stress used to induce senescence in defining the appropriate molecular response. Together, our findings pave the road towards defining the cellular signature of senescent cells in a specific physio pathological context and describe new targetable senescent cell surface proteins.