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A BRET system is described, in which Nanoluciferase was fused to the lipid transfer protein CERT for efficient energy transfer to a Nile red‐labeled ceramide, which is either directly bound to CERT or transported to the adjacent Golgi membrane. Bulk formation of sphingomyelin, a major plasma membrane component in mammals, is dependent on CERT‐mediated transfer of its predecessor ceramide. CERT is considered a promising drug target but no direct cell‐based methods exist to efficiently identify inhibitors. The utility of the method was demonstrated by a library of 140 derivatives of the CERT inhibitor HPA‐12. These were obtained in a combinatorial synthesis using solid‐phase transacylation. Screening of the library led to six compounds that were picked and confirmed to be superior to HPA‐12 in a subsequent dose‐response study and also in an orthogonal lipidomics analysis. [ABSTRACT FROM AUTHOR]