The role of the tumor-infiltrating lymphocyte (TIL) and its relationship to prognosis has been most extensively studied in malignant melanoma. The purpose of this chapter is to discuss in depth the immunobiology and molecular aspects of lymphocyte function in general and particularly TIL function in the context of antimelanoma immunity. Emphasis is placed upon the role of these inflammatory mediators in the enhancement and impairment of progression of this often fatal human cancer. In addition, the analysis of TILs in melanoma and their direct relationship to prognosis as well as their effect on the positivity of the sentinel lymph node will be discussed. Furthermore, details of lymph node responses to metastatic melanomas and their prognostic significance will be clarified. Finally, the importance of TILs for the evaluation of therapeutic response and how TIL immunobiology could critically inform the design of novel melanoma immunotherapeutic protocols will be elucidated.