Angular dependence of x-ray fluorescence (ADXRF), x-ray absorption fine structure (XAFS), and grazing incidence x-ray scattering measurements were carried out using synchrotron radiation for a study of the interface morphology and migration of constituent atoms in a heterojunction formed between CdS and CuInSe2 single crystals. The advantage of using a single crystal for this study is to avoid the usually complicated problems arising from multiple phases of the Cu–In–Se compounds. By a comparison of the results obtained with a bare CuInSe2 single crystal, the changes of interface microstructures in the CdS/CuInSe2 heterojunction system with well-defined stoichiometry can therefore be investigated. Prominent features in the ADXRF data clearly demonstrate that both Cu and Se atoms have migrated into the CdS layer in the heterojunction while In atoms remain intact in the CuInSe2 single crystal. The local structures around Cu in the system also show a significant change after the deposition of CdS, as manifested by the appearance of new Cd near neighbors in the XAFS spectra.