With increasing evidence that senescent cells are detrimental towards a range of age-associated diseases and physiologic declines, there is rising urgency to develop interventions to suppress their adverse effects. Most senolytic approaches aim to eliminate senescent cells by rendering them vulnerable to apoptosis, while senostatic (senomorphic) approaches do not destroy the cell and instead suppress a specific senescent trait. In both senolysis and senostasis, the major goals include reducing the senescence-associated secretory phenotype (SASP) and to enhance the immunogenicity of the senescent compartment. These therapeutic aims are best elicited from the plasma membrane, although efforts to identify plasma membrane targets are only now beginning. We discuss several plasma membrane proteins expressed preferentially in senescent cells and their roles in neutralizing senescent cells by immune-mediated senolysis (as reported for DPP4, VIM, and NKFB2 ligands) and by suppressing the SASP (as reported for SCAMP4 and CD36). We identify the advantages and challenges of developing therapeutic approaches directed at the plasma membrane of senescent cells.