Early diagnosis and treatment are critical to minimize the spread and to reduce morbidity and mortality from tuberculosis. Clinical diagnosis is most time difficult resulting from non-specific and frequently indolent symptoms. Radiological presentation may be very diverse. Currently TB diagnosis still depends on microbiological exams which require a very careful and quick specimen handling. A positive acid-fast bacilli smear makes a rapid presumptive diagnosis. Nevertheless the gold-standard for diagnosis still is cultural-isolation of the Mycobacterium tuberculosis, which may take several weeks to attain. Biochemical (adenosine deaminase) and molecular techniques (nucleic acid amplification tests) are already approved for tuberculosis diagnosis and can provide rapid diagnostic information to the clinician. Numerous alternative diagnostic methods are still under experimentation but none of them has a recognized role. In most cases diagnosis of tuberculosis lays on an adequate combination of different diagnostic methods which is time-consuming. Even though in some cases laboratory confirmation is never obtained and diagnosis and treatment is established on suspicious basis. The purpose of this paper is to discuss the utility of the several diagnostic methods currently available and to point out most common difficulties found by the clinicians to the correct and timely diagnosis.