Anti-tumor T cells are the soldiers in the body's war against cancer. Effector T cells can detect and eliminate cells expressing their cognate antigen via activation through engagement of the T cell receptor (TCR) with its cognate peptide:MHC complex. Owing to the recent success of immunotherapy in the treatment of many different cancer types, research efforts have shifted toward identifying and tracking anti-tumor T cell responses upon treatment in cancer patients. While traditional methods, such as ELISpot and flow cytometric intracellular staining have had limited success, likely owing to the inability to get viable biospecimens or the lower magnitude of tumor-specific T cell responses relative to virus-specific responses, new techniques that utilize next generation sequencing enable T cell response tracking independent of cytokine production or cell viability. The TCR, which confers T cell antigen-specificity, can be used as a molecular barcode to track T cell clonotypic dynamics across biological compartments and over time in cancer patients undergoing treatment. Because this method does not require viable cells, these T cell clonotypes can also be tracked in archival tumor tissue and flash frozen cell pellets. While exciting, quantitative TCR sequencing (TCRseq) technologies have been met with the conundrum of how to properly analyze and interpret the data. Here we provide a comprehensive guide on how to acquire, analyze, and interpret TCRseq data, as well as special considerations that should be taken prior to experimental setup.