Mycobacteria are a group of aerobic, non-motile, acid fast bacteria that have a characteristic cell wall composed of a mycolyl-arabinogalactan-peptidoglycan complex. They display different phenotypic attributes in their growth, color and biochemistry. Tuberculosis (TB) is defined as the infection with Mycobacterium tuberculosis complex and was declared a global health emergency principally because of the appearance of multidrug-resistant strains and the associated risk of infection in immune-compromised population. There is an urgent clinical need for novel, potent and safe anti-TB drugs. Natural products have been used since antiquity for treating diverse complaints and novel pharmacophores are discovered every year. Two of the most potent used antimycobacterials, the rifamycins and streptomycin, were first detected in Streptomyces bacteria. Plants are also the source of an exquisite variety of antimicrobials that can lead to useful therapeutics in the future. In this review, natural preparations used since antiquity for treating tuberculosis are described, together with a rapid view of the 20th century antibiotic development against TB. Finally a summary of the most potent recent natural antimycobacterials is displayed.