Tuberculosis (TB) is one of the oldest infectious diseases known to man and has infected one third of the world’s population. As a result, someone dies from the disease every 15 seconds and 30 million more people will lose their lives to TB in the next decade. Although directly observed short course chemotherapy (DOTS) is available to treat the disease, this treatment is old, slow and inefficient by the current standards of the pharmaceutical industry. In recent years, with increased public and private funding, some of the most innovative approaches have been used to identify and validate targets for new drugs, and to implement the screening and medicinal chemistry processes required to identify lead compounds for the generation of candidate drugs. New TB drugs should have the following desired properties: 1) High potency to reduce treatment duration, 2) Activity against persistent bacilli, 3) Inhibition of new target classes, 4) Activity against multidrug resistant TB, 5) Specificity for Mycobacterium tuberculosis. Among the validated targets that we are pursuing in the NM4TB project, as part of the European Commission’s 6th Framework programme, are several enzymes involved in highly druggable areas such as cell wall biogenesis, nucleic acid synthesis and central metabolic pathways for which assays amenable to high-throughput screening are available. Intensive efforts are being focused on rapidly emerging targets that impact upon two as-yet untouched areas of the physiology of M. tuberculosis namely signal transduction pathways and persistence. Details of the former will be presented.