CD137 (4-1BB) is a member of the TNFR-family with costimulatory function, triggering prosurvival signals in activated T-cells. Upregulation of CD137 upon stimulation allows identifying and isolating live, human antigen-specific CD8+ T-cells of all phenotypes, and therefore provides a comprehensive detection method. Furthermore responses against antigen mixtures can be easily detected, enabling antigen discovery in a stepwise deconvoluting approach. In this article, we will discuss various aspects of this methodology, including potential pitfalls as well as a variety of applications, as illustrated by examples from our laboratory.