Tuberculosis (TB) remains a major global health concern, with nearly 4000 deaths daily. The only licensed TB vaccine, BCG, provides variable protection against adult pulmonary TB. Over the past 20 years, efforts have focused on developing new TB vaccines, but conventional preclinical models have failed to fully replicate human responses. This review outlines strategies for identifying protective mycobacterial antigens and recent advancements in preclinical models for evaluating TB vaccine efficacy. TB vaccine development has primarily focused on identifying secreted culture filtrate (CF) antigens, which are key protective antigens. Studies have identified several immunogenic proteins, including Ag85 complex proteins, ESAT-6, and CFP-10. These antigens are important for disease establishment in animal models and are being evaluated in clinical trials. Dormancy antigens and resuscitation promoting factors are also promising vaccine targets. For example, HspX, a latency antigen, has shown robust immunogenicity in animal models and is being used as a candidate vaccine antigen. Recent studies have demonstrated that antibodies against different surface antigens can provide moderate protection against TB in preclinical animal models. Multi-antigenic vectored vaccines, which combine latency antigens with classical early secreted antigens and resuscitation promoting factors, have shown strong vaccine potential. Immunization of rhesus macaques with a cytomegalovirus-based vaccine provided unprecedented protection against TB disease. In silico approaches have accelerated vaccine design by enabling epitope prediction and selection of immunogenic antigens. Computational vaccinology has facilitated the identification of potential candidate vaccine antigens using comprehensive data mining and in silico tools. These approaches have identified several promising antigens, including those from the DosR regulon and resuscitation phase antigens. Other genome-wide approaches have identified genes differentially expressed during in vivo infection with M. tuberculosis. These genes, such as Rv2034, have been evaluated as vaccine candidates in mice and guinea pigs. The identification of immunodominant CD8 T-cell antigens has also been a focus of research, with several antigens being evaluated in clinical trials. Recent advancements in single cell T-cell receptor sequencing technologies and improved in silico analytical tools have allowed unprecedented throughput and efficiency in profiling TCR specificities. These technologies have identified putative protective and non-protective TCR similarity groups, highlighting the need for systematic screening of T-cell specificities and TB outcomes. Immunopeptidomics has been used to identify MHC-bound peptide epitopes, providing insights into the antigens presented by M. tuberculosis. These studies have identified several new antigens that may be useful in vaccine development. Mycobacterial lipid antigens are also attractive candidates for subunit TB vaccine development. Studies have shown that immunization with lipid antigens provides modest protection against TB challenge. Multi-component subunit vaccines combining protein and lipid antigens may holdTuberculosis (TB) remains a major global health concern, with nearly 4000 deaths daily. The only licensed TB vaccine, BCG, provides variable protection against adult pulmonary TB. Over the past 20 years, efforts have focused on developing new TB vaccines, but conventional preclinical models have failed to fully replicate human responses. This review outlines strategies for identifying protective mycobacterial antigens and recent advancements in preclinical models for evaluating TB vaccine efficacy. TB vaccine development has primarily focused on identifying secreted culture filtrate (CF) antigens, which are key protective antigens. Studies have identified several immunogenic proteins, including Ag85 complex proteins, ESAT-6, and CFP-10. These antigens are important for disease establishment in animal models and are being evaluated in clinical trials. Dormancy antigens and resuscitation promoting factors are also promising vaccine targets. For example, HspX, a latency antigen, has shown robust immunogenicity in animal models and is being used as a candidate vaccine antigen. Recent studies have demonstrated that antibodies against different surface antigens can provide moderate protection against TB in preclinical animal models. Multi-antigenic vectored vaccines, which combine latency antigens with classical early secreted antigens and resuscitation promoting factors, have shown strong vaccine potential. Immunization of rhesus macaques with a cytomegalovirus-based vaccine provided unprecedented protection against TB disease. In silico approaches have accelerated vaccine design by enabling epitope prediction and selection of immunogenic antigens. Computational vaccinology has facilitated the identification of potential candidate vaccine antigens using comprehensive data mining and in silico tools. These approaches have identified several promising antigens, including those from the DosR regulon and resuscitation phase antigens. Other genome-wide approaches have identified genes differentially expressed during in vivo infection with M. tuberculosis. These genes, such as Rv2034, have been evaluated as vaccine candidates in mice and guinea pigs. The identification of immunodominant CD8 T-cell antigens has also been a focus of research, with several antigens being evaluated in clinical trials. Recent advancements in single cell T-cell receptor sequencing technologies and improved in silico analytical tools have allowed unprecedented throughput and efficiency in profiling TCR specificities. These technologies have identified putative protective and non-protective TCR similarity groups, highlighting the need for systematic screening of T-cell specificities and TB outcomes. Immunopeptidomics has been used to identify MHC-bound peptide epitopes, providing insights into the antigens presented by M. tuberculosis. These studies have identified several new antigens that may be useful in vaccine development. Mycobacterial lipid antigens are also attractive candidates for subunit TB vaccine development. Studies have shown that immunization with lipid antigens provides modest protection against TB challenge. Multi-component subunit vaccines combining protein and lipid antigens may hold