Neoadjuvant immune-checkpoint inhibition is a promising emerging treatment approach for patients with surgically resectable macroscopic stage III melanoma. The neoadjuvant setting provides an ideal platform for personalized therapy owing to the very homogeneous nature of the patient population and the opportunity for pathological response assessments within several weeks of starting treatment, thereby facilitating the efficient identification of novel biomarkers. A pathological response to immune-checkpoint inhibitors has been shown to be a strong surrogate marker of both recurrence-free survival and overall survival, enabling timely analyses of the efficacy of novel therapies in patients with early stage disease. Patients with a major pathological response (defined as the presence of ≤10% viable tumour cells) have a very low risk of recurrence, which offers an opportunity to adjust the extent of surgery and any subsequent adjuvant therapy and follow-up monitoring. Conversely, patients who have only a partial pathological response or who do not respond to neoadjuvant therapy still might benefit from therapy escalation and/or class switch during adjuvant therapy. In this Review, we outline the concept of a fully personalized neoadjuvant treatment approach exemplified by the current developments in neoadjuvant therapy for patients with resectable melanoma, which could provide a template for the development of similar approaches for patients with other immune-responsive cancers in the near future.