Mycobacterial infections and tuberculosis pose global public health threats. High tuberculosis morbidities and mortalities are due to the diagnosis problems among other causes. This chapter describes and compares diverse mycobacterial infections and tuberculosis diagnostic efforts and point-out the direction so as to inform areas of and motivate research toward early, rapid, and accurate diagnosis for effective TB control. We have grouped diagnostic approaches according to the type of sample taken for or organ targeted during diagnosis. The sputum-based methods include smear microscopy, culture, and rat sniffing. Interferon-γ (INF-γ) release assays, transcriptional blood signatures, and proteomic profiling use blood samples while colorimetric sensor array (CSA) and mass spectrometry use urine samples. Patho-physiological methods include tuberculin skin tests (TSTs) and radiography. Chromatography and acoustic wave detection can also be used to diagnose TB from breath. Comparative description of these methods is based on a time frame to diagnosis, accuracy, cost, and convenience. The trend shows that there is a move from time-consuming, slow and narrow-spectrum to quick and broad-spectrum TB diagnostic procedures. The sputum-based and patho-physiological approaches remain conformist while blood-based procedures lead research developments. Absence of single best approach calls for synergistic research combinations that form accurate, rapid, cheap, and convenient package at point-of-care centers.