As active screening strategies for tuberculosis (TB) continue to rise globally, it has become increasingly important to consider the methodological challenges in designing and implementing these strategies. The key challenges associated with TB screening can be summarized in terms of four continua or spectra, namely those of 1) TB disease and diagnostic yield, 2) TB risk and resource availability, 3) TB screening strategies, and 4) outcomes and impact measurements of screening programs. In this review, we provide a discussion of these challenges to help guide development of TB screening strategies that will be effective in a given epidemiological setting.