Immunofocusing is a strategy to create immunogens that direct humoral immune responses toward a specific epitope, away from non-desirable ones. It aims to develop "universal" vaccines against highly variant viruses like influenza, HIV-1, and SARS-CoV-2. Five main immunofocusing strategies are discussed: cross-strain boosting, mosaic display, protein dissection, epitope scaffolding, and epitope masking. Challenges include immune imprinting and immunodominance, where antibodies target specific epitopes, often leading to strain-specific responses. Broadly neutralizing antibodies (bnAbs) are rare and difficult to elicit, as they target conserved regions of viral proteins. Immunofocusing seeks to overcome these by reducing responses to off-target epitopes and enhancing responses to desired ones. Cross-strain boosting involves sequential immunization with antigenically distinct versions of the same protein to enhance cross-reactive B cell responses. Mosaic display uses multivalent scaffolds with antigenically distinct versions of a protein to stimulate cross-reactive B cells. Protein dissection removes unwanted epitopes through engineering, while epitope scaffolding translocates the target epitope to a different scaffold. Epitope masking uses biochemical modifications to shield off-target epitopes. Each method has its challenges, such as the need for high-resolution immunogens and the risk of off-target responses. Synergies between methods, like combining hyperglycosylation and PMD (protect, modify, deprotect), can enhance resolution. Immunofocusing is crucial for developing vaccines against future viral outbreaks, especially as seen in the SARS-CoV-2 pandemic. Advances in computational methods and protein design will further improve immunofocused vaccine development. The choice of method depends on the antigen, with some requiring higher resolution for complex epitopes. Overall, immunofocusing holds promise for creating high-resolution vaccines that provide broad protection against evolving viral threats.Immunofocusing is a strategy to create immunogens that direct humoral immune responses toward a specific epitope, away from non-desirable ones. It aims to develop "universal" vaccines against highly variant viruses like influenza, HIV-1, and SARS-CoV-2. Five main immunofocusing strategies are discussed: cross-strain boosting, mosaic display, protein dissection, epitope scaffolding, and epitope masking. Challenges include immune imprinting and immunodominance, where antibodies target specific epitopes, often leading to strain-specific responses. Broadly neutralizing antibodies (bnAbs) are rare and difficult to elicit, as they target conserved regions of viral proteins. Immunofocusing seeks to overcome these by reducing responses to off-target epitopes and enhancing responses to desired ones. Cross-strain boosting involves sequential immunization with antigenically distinct versions of the same protein to enhance cross-reactive B cell responses. Mosaic display uses multivalent scaffolds with antigenically distinct versions of a protein to stimulate cross-reactive B cells. Protein dissection removes unwanted epitopes through engineering, while epitope scaffolding translocates the target epitope to a different scaffold. Epitope masking uses biochemical modifications to shield off-target epitopes. Each method has its challenges, such as the need for high-resolution immunogens and the risk of off-target responses. Synergies between methods, like combining hyperglycosylation and PMD (protect, modify, deprotect), can enhance resolution. Immunofocusing is crucial for developing vaccines against future viral outbreaks, especially as seen in the SARS-CoV-2 pandemic. Advances in computational methods and protein design will further improve immunofocused vaccine development. The choice of method depends on the antigen, with some requiring higher resolution for complex epitopes. Overall, immunofocusing holds promise for creating high-resolution vaccines that provide broad protection against evolving viral threats.