The impact of natural products on the well being of mankind has been enormous, and their study continues to influence research in the fields of chemistry, biology, and ecology. Historically, the majority of our medicines originate from natural products and their synthetic derivatives, many of which have taught us valuable lessons about biology. While advances in synthetic and combinatorial chemistry have given rise to notable successes in the development of new drugs, the perceived value of natural products has not waned when it comes to treating infectious diseases. In this Miniperspective, we review the role natural products have played in the treatment of tuberculosis (TBa), their value and limitations as chemical probes, the challenges associated with TB drug development, and the current status of natural product and synthetic small molecules as new TB drug leads.