One of the major efforts for the next generation vaccine for tuberculosis prevention is based upon bacillus Calmette-Guérin (BCG). The potential limitations and practical concerns regarding “new generation tuberculosis vaccine based on BCG” are presented in this paper. The practical challenge in designing, the concerns for preclinical pharmacodynamic evaluation and effective clinical evaluation are discussed. We concluded that although a new BCG-based vaccine may reach the goal for better protection than the current BCG, it is difficult to significantly improve the protection for adults. The trials of new vaccines in newborns may not be conducted due to the ethical issues. Control of latent tuberculosis infection is a key step for the prevention of tuberculosis and the new vaccines may not be applied in this population. Therefore, we need new strategies for new generation of mainstream tuberculosis vaccines as there are significant hurdles on the path for BCG-based research and development.