Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, continues to pose a significant health problem. RNA polymerase, the enzyme responsible for all transcription in bacteria, is a proven and effective target for antimicrobials and is one of the primary targets for antimicrobial treatment of TB. We use a combination of biophysical approaches to study the mycobacterial transcription cycle to aid in the development of new antibiotics to treat TB and to further our understanding of transcription.