Cell free protein synthesis is a valuable tool to profile heterologous expression conditions, generate molecules that could be toxic to the host, and a variety of other valuable applications in natural product discovery and biomanufacturing, however limitations exist for applying cell free expression systems to proteins that are difficult to synthesize in vivo.  Examples include polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs), particularly when derived from genes of actinobacterial or myxobacterial origin.  Because of the large size, high GC content, and/or precursor demands of biosynthetic genes, they are not always efficiently produced in cell free systems. To date, most of the optimisations of cell free expression have been performed with fluorescent protein reporters.  Efforts in our laboratory seek to use reporters that are more relevant to natural product production with particular focus on an NRPS, BpsA which generates the blue pigment indigiodine, and a type III PKS, RppA which generates the red pigment flaviolin.  Lysate based expression systems can be applied to profile novel host machineries, characterise biological parts, understand engineered pathway designs, and ultimately generate new natural product analogs.