Stewart Cole and colleagues determined the complete genome sequence of Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), in 1998 [1]. This was a landmark achievement that heralded a new age in TB drug discovery. With the genome sequence in hand, drug discoverers suddenly had thousands of new potential targets to explore. But the excitement has since faded [2]. It is unquestioned that genomics has transformed our understanding of the biology of this pathogen. However, the expectation that the Mtb genome sequence would rapidly lead to new therapeutic interventions remains unfulfilled [3]. One of the (many) reasons for this unrealized potential is that our tools to systematically interrogate the Mtb genome and its drug targets-so-called functional genomics-have been limited. In this Pearl, I argue that the recent development of robust CRISPR-based genetics in Mtb [4] overcomes many prior limitations and holds the potential to close the gap between genomics and TB drug discovery.