Genomics-inspired isolation led to the identification of two new natural congeneric <i>C</i><sub>2</sub>-asymmetric macrodiolide immunosuppressants, named efophylins A (<b>1</b>) and B (<b>2</b>), from <i>Streptomyces malaysiensis</i> DSM 4137. Their structures were elucidated by spectroscopic and computational methods and were in agreement with biosynthetic predictions from the efophylin gene cluster. Compound <b>2</b> exhibited potent immunosuppressive activity and demonstrated to inhibit the activation of the NFAT and block NFAT dephosphorylation <i>in vitro</i>. The immunosuppressive activity of compound <b>2</b> is possibly at least in part via the CaN/NFAT signaling pathway.