The bacterial genus Streptomyces has long been appreciated for its ability to produce various kinds of medically important secondary metabolites, such as antibiotics, anti-cancer agents, immunosuppressants, and enzyme inhibitors. A secondary metabolite produced by Streptomyces sp. CK4412, originally isolated in Jeju Island, Korea, has been identified as an activated T cell-specific immunosuppressive compound with a novel mode of pharmacological action, both in vivo and in vitro, and whose chemical structure has been shown to be identical to that of a previously reported tautomycetin (TMC), an antifungal compound with a structurally-unique ester bond linkage between a terminal cyclic anhydride moiety and a linear polyketide chain. Inhibition of T cell proliferation with TMC was observed at concentrations 100-fold lower than those needed to achieve maximal inhibition with the best-known immuno-suppressant, cyclosporine A. TMC is believed to specifically block tyrosine phosphorylation of intracellular signal mediators downstream of Src tyrosin kinases in a T cell-specific manner via selective inhibition of PP1/PP2A, leading to apoptosis due to cleavage of Bcl-2, caspase-9, caspase-1. Recently, the Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is proposed to be a target of the immunosuppressant TMC. Moreover, TMC is also reported to inhibit not only growth of colorectal cancer cells through p21cip/WAF1 induction via the extracelluar signal-regulated kinase pathway but also suppress the growth of medullary thyroid cancer cells via inhibition of glycogen synthase kinase-3β, implying that TMC is indeed a potentially-valuable immunosuppressive and anticancer drug lead compound. Unlike a TMC-like non-immunosupressant PP1/PP2A inhibitor, tautomycin (TM), TMC exhibits an extremely high degree of selectivity toward PP1 over PP2A. TMC was shown to preferentially inhibit PP1 by a factor of ~40-fold relative to PP2A, while TM shows no significant selectivity toward either PP1 or PP2A. Considering that both TMC and TM have identical anhydride moieties yet slightly-different linear polyketide chain structures, it is reasonable to hypothesize that both PP1 and immunosuppressive specificities come from unique and functional groups attached to the TMC linear polyketide moiety. Despite considerable gains over the past few years, the full promise of TMC to become a novel immunosuppressive and anticancer lead compound and to be developed as useful pharmaceutical will only be realized by closing a series of key gaps in knowledge and technology. To solve these challenges, we are currently focusing on molecular biotechnological researches, 1) to understand the detailed biosynthetic and regulatory steps involved in assembly of the TMC linear polyketide chain leading to the production of various novel TMC analogs using targeted domain alternations, 2) to reveal relationship between linear structure and biological specificity of TMC polyketide moiety through chemoenzymatic and bioassay-based approaches, and finally 3) to rationally redesign several potentially-valuable and pharmacokinetically-superior TMC-derived novel analogs through systems and synthetic biotechnologies.