Tuberculosis (TB) is an epidemic disease and the growing burden of multidrug-resistant (MDR) TB world wide underlines the need to discover new drugs to treat the disease. Mycobacterium tuberculosis (Mtb) is the etiological agent of most cases of TB. Mtb is difficult to treat, in part, due to the presence of a sturdy hydrophobic barrier that prevents penetration of drugs through the cell wall. Mtb can also survive in a non-replicative state for long periods of time avoiding the action of common antibiotics. Trehalose is an essential metabolite in mycobacteria since it plays key roles in cell wall synthesis, transport of cell wall glycolipids, and energy storage. It is also known for its stress protective roles such as: protection from desiccation, freezing, starvation and osmotic stress in bacteria. In this review we discuss the drug discovery efforts against enzymes involved in the trehalose utilization pathways (TUPs) and their likelihood of becoming drug targets.