Platensimycin (PTM) and platencin (PTN) are potent inhibitors of the type II fatty acid synthase, serving as excellent leads for new antibacterial antibiotic discovery and development.  We have cloned and sequenced the gene clusters for PTM and PTN biosynthesis from Streptomyces platensis MA7327 and MA7339, respectively, and in vivo and in vitro characterizations of PTM and PTN biosynthetic machineries have unveiled many unprecedented features for natural product biosynthesis and engineering.  Selected results from our current studies on PTM and PTN biosynthesis and engineering will be discussed, including (i) comparative analysis of the PTM and PTN biosynthetic machineries, (ii) selected enzymes catalyzing novel chemistry, (iii) mechanism of PTM and PTN resistance, and (iv) application of combinatorial biosynthesis methods to the PTM and PTN biosynthetic machineries for titer improvement and novel analog engineering will be discussed.