<p>Anti-PD-L1 antibodies have transformed cancer treatment and are increasingly being used in patients with early-stage malignancies including in the adjuvant and neoadjuvant settings. In certain cancers, earlier administration of these agents reduces the risk of metastatic disease and might improve overall survival. Thus far, however, overall survival benefits in the adjuvant setting have yet to be clearly demonstrated in all tumour types probably owing to a lack of long-term follow-up and/or the confounding effects of anti-PD-L1 antibody monotherapy and/or combinations in the metastatic setting, in which these agents can also produce durable responses. In this Review, we explore the optimal use of anti-PD-L1 antibodies in the adjuvant and perioperative settings, using examples from melanoma, renal cell carcinoma and non-small-cell lung cancer. We examine de-escalation strategies, including shortening treatment duration or deferring therapy to time of recurrence, at which point anti-PD-L1 antibodies might be more likely to be administered in combination; the expansion of certain specific indications, potentially leading to more effective combinations and/or use in biomarker-defined patients with high-risk early-stage disease; and selecting the most appropriate indication, with emerging data suggesting that neoadjuvant or perioperative use of anti-PD-L1 antibodies might be more effective than adjuvant use in certain cancers, as well as the possibility of personalization of therapy guided by biomarkers such as circulating tumour DNA or other emerging assays.</p>