Antitubercular Fixed Dose Combinations (FDCs) containing rifampicin (RIF) along with Isoniazid (INH), And/or pyrazinamide (PZ) and/or ethambutol (ETB) ensure better patient compliance and help to minimize development of resistance to the drugs by M. tuberculosis. However, poor bioavailability of RIF In these FDC formulations is a subject of much concern for the last three decades. Poor bioavailability of RIF could lead to faulty treatment and to the drug resistance. WHO and IUATLD have now sounded a caution that antitubercular FDC formulations should be used only if the bioavailability of RIF has been demonstrated convincingly. It has been suggested that probable physical factors responsible for the variable bioavailability of RIF include particle size, crystalline nature, nature of excipients and lack of GMP. However, nine of these explanations are found to be satisfactory. During the last few years, sufficient data has been generated, independently, in two Indian research laboratories, indicating that in the acidic medium of the stomach, RIF degrades to form an insoluble and inactive 3-formyl rifamycin SV, an aldehyde, involving a distinct catalytic role of INH. An elegant reaction mechanism has been proposed for the impaired bioavailability of RIF from FDC formulations containing INH. With a better understanding of the interaction of RIF and INH in the acidic medium, it should now be possible to formulate a stable FDC with acceptable and reproducible bioavailability of RIF.