Tumor-infiltrating lymphocytes (TILs), through displaying a T-cell receptor (TCR) repertoire as heterogeneous as that of normal peripheral blood T cells, show overexpression of TCR variable-gene segments that include clonally expanded TCR sequences. Here, Marialuisa Sensi and Giorgio Parmiani analyze the available information on TCR usage by T cells present in the infiltrate of histologically different tumors and suggest that the analysis of TCR sequences represents a powerful new tool to assess the in vivo immune response to growing tumors. Ultimately, this strategy may lead to the identification and manipulation of T-cell populations endowed with antitumor reactivity.