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Excellent thermoelectric materials need both high carrier transport properties and low phonon transport properties simultaneously, which make it challenging to enhance thermoelectric performance. However, recent progress shows that sub-nanostructures can strongly intensify phonon scattering but scarcely impede carrier mobility, thus effectively contributing to high thermoelectric performance in PbTe/Se-based systems. In this perspective, we summarize the thermoelectric transport properties and internal atomic-scale structures in these PbTe/Se-based systems with sub-nanostructures. Then, their thermoelectric properties are comprehensively compared with other massively nanostructured PbTe/Se-based systems, reveling the favorable role of sub-nanostructures in achieving high carrier mobility. Finally, several other potential strategies to further maintain carrier transport properties and enhance thermoelectric performance are proposed, which might be extended to other thermoelectric systems.