A strategy for encapsulating hydrophobic organic entities in aqueous solution has been developed through use of a self-assembling heterotelechelic amphiphilic random copolymer. The polymer (∼40 kDa), prepared by living radical polymerization, contains orthogonally reactive terminal groups and pendant hydrophobic (dodecyl), nonionic hydrophilic (PEG9), and ionic hydrophilic (sulfonate-terminated) groups. Covalent conjugation of a hydrophobic entity to the polymer terminus has been demonstrated for 8 classes of organic fluorophores. The resulting “pod-fluorophore” architecture is unimeric (∼15 nm in diameter) in aqueous solution with spectral features and fluorescence brightness resembling those of the benchmark fluorophore in organic solution. This strategy separates the functional design of the packaged molecular entity (“cargo”) from the often vexing challenge of water solubilization and in so doing creates a unitary (one-pod–one-cargo) platform architecture for potential applications in cytometry, biomedical imaging, environmental sensing, and supramolecular chemistry.