<jats:title>Abstract</jats:title><jats:p>Two new peptidic proteasome inhibitors were isolated as trace components from a Curaçao collection of the marine cyanobacterium <jats:italic>Symploca</jats:italic> sp. Carmaphycin A (<jats:bold>1</jats:bold>) and carmaphycin B (<jats:bold>2</jats:bold>) feature a leucine‐derived α,β‐epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR and MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the β5 subunit (chymotrypsin‐like activity) of the <jats:italic>S. cerevisiae</jats:italic> 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell‐line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.