Study of NK cell receptor signaling in mouse NK cells has been difficult since there are no clones of murine NK cells. We describe here a model system that overcomes this problem. This system allows the study of many aspects of NK cell receptor function with complete control over the variables that may affect activity such as cis versus trans ligand engagement, homotypic interactions, multiple target types, receptor number, receptor-ligand affinity, and signaling adaptor molecule expression. Although we give examples only for 2B4, Ly49C, and CD48, any NK cell receptors could be studied using these methods. Since many NK cell receptors such as 2B4, CD48, and the Ly49 family can be expressed in T cells, this model system allows the study of not only NK cells but also T cells with NK cell receptors. A standardized system for determining the regulation of NK cell receptor signaling can be important for understanding the anti-tumor activities of NK cells.