The cell envelope of Mycobacterium tuberculosis (Mtb) possesses a repertoire of unusual lipids that are believed to play an important role in pathogenesis. In this review, we specifically focus on computational, biochemical and structural studies in lipid biosynthesis that have established functional role of polyketide synthases (PKSs) and fatty acyl-AMP ligases (FAALs). Mechanistic and structural studies with FAALs suggest that this group of proteins may have evolved from omnipresent fatty acyl-CoA ligases (FACLs). FAALs activate fatty acids as acyl-adenylates and transfer them on to the PKSs which then produce unusual acyl chains that are the components of mycobacterial lipids. FAALs are a newly discovered family of enzymes; whereas involvement of PKSs in lipid metabolism was not known prior to their discovery in Mtb. Since Mtb genome contains multiple homologs of FAALs and PKSs and owing to the conserved reaction mechanism and overlapping substrate specificity; there is tempting opportunity to develop ‘systemic drugs’ against these enzymes as anti-tuberculosis agents.