Substrate clamping and inter-domain pinning limit movement of non-180 degrees domain walls in ferroelectric epitaxial films thereby reducing the resulting piezoelectric response of ferroelectric layers. Our theoretical calculations and experimental studies of the epitaxial PbZrxTi1-xO3 films grown on single crystal SrTiO3 demonstrate that for film compositions near the morphotropic phase boundary it is posssible to obtain mobile two-domain architectures by selecting the appropriate substrate orientation. Transmission electron microscopy, X-ray diffraction analysis, and piezoelectric force microscopy revealed that the PbZr0.52Ti0.48O3 films grown on (101) SrTiO3 substrates feature self-assembled two-domain structures, consisting of two tetragonal domain variants. For these films, the low-field piezoelectric coefficient measured in the direction normal to the film surface (d(33)) is 200 pm V-1, which agrees well with the theoretical predictions. Under external AC electric fields of about 30 kV cm(-1), the (101) films exhibit reversible longitudinal strains as high as 0.35 %, which correspond to the effective piezoelectric coefficients in the order of 1000 pm V-1 and can be explained by elastic softening of the PbZrxTi1-xO3 ferroelectrics near the morphotropic phase boundary.