Semiconducting single-crystal thin films of PbSe and chemically prethinned samples of bulk Si were found to be suitable substrate materials for in situ TEM studies of autoepitaxial and heteroepitaxial film nucleation and growth processes. In situ surface cleaning by either evaporation or sputtering was used in conjunction with a UHV background environment to ensure reliable results. The epitaxial systems which have been studied most extensively are Au and Ag on (100)-oriented PbSe. Detailed results obtained include (a) identification of structure (polymorphism), crystalline perfection, and stoichiometry of the initial and the autoepitaxially thickened PbSe substrates; (b) quantitative nucleation and growth kinetic measurements at low supersaturation of Ag on PbSe—a system characterized by weak interaction energies and high surface mobilities; (c) observations of epitaxial orientations and the development of epitaxy during the deposition process; and (d) demonstration of strong substrate/overgrowth reactions involving alloying and interdiffusion.