The differentiation-inducer activity of a series of derivatives modified on the terminal ring, the polyene side-chain or the polar end group of the retinoic acid molecule was tested on the human histiocytic lymphoma cell line U-937 and compared with that of all-trans-retinoic acid. Only retinoids with both an unsaturated terminal end ring and a free carboxyl polar end group were found to be active in this system. Introduction of an aromatic ring in place of the first double bond of the side chain increased highly the activity whereas cyclisation of the last two double bonds decreased it. Replacement of the unsaturated terminal ring by an aromatic ring abolished the activity as did the esterification of the carboxyl end group or its replacement by a sodium sulfinate, sodium sulfonate or ethyl sulfone end group. All but only the active retinoids induced the same morphological and biochemical changes on U-937 cells, suggesting that they have the same route of action. However, biologically inactive retinoids were shown to be able to inhibit the differentiation of U-937 cells, induced by active ones, indicating that they can compete for a common "receptor".