The rigorous evaluation of cancer vaccination requires evidence of benefit to patients with cancer or those at risk of relapse from the disease. Clinical trials are expensive and require considerable human and clinical resources in order to demonstrate this benefit. In the era of defined cancer antigens, it is possible to evaluate immunogenic targets, and assess the quality and magnitude of immune responses against these antigens following vaccination. Analyzing these surrogate end points complements clinical assessment and provides a depth of understanding to better inform trial evaluation and design. We have used the immunogenic cancer testis antigen NY-ESO-1 as a model antigen. This article summarizes our experience in monitoring immunity against NY-ESO-1.