Infections by the human immunodeficiency virus (HIV-1) and Mycobacterium tuberculosis (MTB) account for tens of millions of deaths per year world wide.  Consequently, there continues to be a need for new therapeutics as well as new targets toward both of these pathogens.  Our group has identified a number of natural products that block the first step of HIV infection, namely HIV entry; as well as compounds that inhibit mycothiol-associated enzymes from MTB and MTB cell growth.  Subsequent to isolation and structure elucidation studies, a major focus in our laboratory is to determine the mechanisms of action of natural product inhibitors and ideally, the structural basis for inhibitor activity.  Studies illustrating examples of these projects will be presented.