Worldwide, tuberculosis (TB) is one of the most important infectious diseases in subjects with HIV infection. Although effective therapy is available for both conditions, there are major problems in the concurrent treatment of HIV and TB co-infection. In this article the knowledge available on drug-drug interactions between anti-HIV and anti-TB compounds is analysed, particularly with regard to pharmacological interactions secondary to interference with cytochrome P450 enzymes. Within the same setting, facts and possible interpretations of the problems encountered in terms of tolerance and safety of the concurrent treatment of TB and HIV are also reviewed. Current guidelines, as well as additional possible strategies to be adopted in this particular co-morbidity setting are discussed.