When a tumor evolves, there is constant crosstalk between the transformed cells and cells of the immune system. Transplantation of well-established tumor cell lines into genetically engineered mice is a valuable tool to study the contribution of a gene of interest to tumor surveillance. These methods bear several advantages: first, such cell lines are well characterized; second, much data for reference exist; and third, the impact of the immune system can be separated from tumor cell intrinsic effects. Here, we provide protocols for tumor cell transplantations to address the role of a specific gene product in tumor surveillance. We furthermore describe several approaches to define the impact of natural killer cells and T cells, such as cell depletion and adoptive transfer experiments or use of different genetically modified mice.