The problem of poor/variable bioavailability of rifampicin, which is shown in particular when the drugs are present in anti-tubercular fixed-dose combination (FDC) products, is a matter of serious concern. There is a potential of failure of therapy in patients with an active disease. It perhaps also is a contributory factor towards the increasing resistance to anti-tubercular drugs. Unfortunately, the origin and cause of the problem is not clearly understood, though GMP and crystalline changes in the drug are invariably cited as the principal reasons. In this write-up, various probable physical and/or chemical reasons are critically reviewed. The enhanced decomposition of rifampicin in the presence of isoniazid in stomach after ingestion is indicated to be the key factor behind the problem. Some simple solutions offered by the knowledge of the cause are discussed and it is concluded that there is a need to have a multifaceted approach to handle the problem.