Human noroviruses are the most common cause of epidemic nonbacterial gastroenteritis in the world. Despite their importance as human pathogens, little is known about how the immune system controls and clears norovirus infection, and the potential and mechanisms of vaccination remain unclear. Here, we used norovirus infection of mice to show that vaccination can provide long-lasting immunity against mucosal norovirus challenge and to identify the types of immune cells that are important in vaccination against norovirus infection. Similarly, we identified the types of immune T cells that are important for clearance of acute infection. Efficient vaccination required all three major arms of adaptive immunity: CD4 T cells, CD8 T cell, and B cells. Importantly, protective vaccination against mucosal challenge was observed after either mucosal or systemic norovirus antigen exposure. The pore-forming molecule perforin was important for T cell-mediated control of norovirus infection. Our study has important implications for understanding adaptive immunity to norovirus infection, and may provide insight into the directions to take in developing a human norovirus vaccine. either MNV1.CW1 (p = 0.0002) or MNV1.CW3 (p = 0.0009) significantly decreased MNV1.CW3 replication in the distal ileum compared to control mice infected with reovirus ( Figure 1B ). Similar decreases were observed in the MLN after vaccination with MNV1.CW1 (p = 0.0001) or MNV1.CW3 (p = 0.0003) ( Figure 1C ) compared to the reovirus controls. Similar results were observed in the spleen (data not shown). There was no statistically significant difference between vaccination with MNV1.CW1 or MNV1.CW3. This demonstrates that a protective secondary immune response develops after clearance of primary MNV infection.