ABSTRACT Mycobacterium tuberculosis (Mtb) is surrounded by one of the thickest and most impenetrable cell walls of any known bacterium. This structure is not unlike that of the outer membrane of gram-negative bacteria but creates a far more extreme permeability barrier for nutrients. Other bacterial species with such an outer membrane generally have porins that allow uptake of water-soluble nutrients, but Mtb and most pathogenic mycobacteria do not. The mechanisms by which Mtb transports nutrients across the outer membrane in the absence of classical porins remain largely unknown. The absence of porins in mycobacterial species is strikingly well correlated with an expansion of proteins belonging to the Pro-Glu (PE) and Pro-Pro-Glu (PPE) protein families. These PE/PPE proteins have been one of the most perplexing puzzles in tuberculosis biology: The 169 family members are scattered throughout the genome, take up ~10% of Mtb’s genetic coding capacity, and are almost exclusively found in pathogenic mycobacteria. Their sequences are highly unusual and characterized by intrinsically disordered repeat regions. Their large number, disordered structure, and unusual length has made the PE/PPE proteins equally difficult to work with by genetic, structural, and biochemical approaches. Over twenty years after their discovery, they remain some of the most intractable proteins and their function remains largely unknown. We and others now discovered an unexpected function of a subset of the PE/PPE proteins as nutrient transporters across the outer membrane of Mtb. Here, we will test the hypothesis that the PE/PPE proteins are a large family of transporters that shuttle nutrients across the Mtb outer membrane and that might also be responsible for drug uptake and efflux, thus affecting Mtb drug resistance.