Mycobacterium tuberculosis (Mtb) is one of the most successful microbial pathogens, and currently infects over a quarter of the world's population. Mtb's success depends on the ability of the bacterium to sense and respond to dynamic and hostile environments within the host, including the ability to regulate bacterial metabolism and interactions with the host immune system. One of the ways Mtb senses and responds to conditions it faces during infection is through the concerted action of multiple cyclic nucleotide signaling pathways. This review will describe how Mtb uses cyclic AMP, cyclic di-AMP and cyclic di-GMP to regulate important physiological processes, and how these signaling pathways can be exploited for the development of novel thereapeutics and vaccines.