In this letter, we report a mesoscopic theory of ferroelectrics to explain the dramatically enhanced piezoelectricity in relaxor ferroelectric single crystals poled along a nonpolar axis, where the coexistence of several variants leads to complicated domain configurations. The engineered domain configuration is constructed first using energy minimization approach, and the effective moduli of single crystals with engineered domain configuration are then determined using the lamination theory. Using this approach, we calculate the effective electromechanical moduli of Pb(Mg1/3Nb2/3)O3–PbTiO3 (PMN-PT) crystals poled along [001] and [011] directions, which agree well with experimental observations. In addition, we demonstrate that PMN-PT crystals electromechanically poled by an electric field along [001] direction and an additional positive shear stress σ12 possess superior electromechanical coupling factors k31 and k33 simultaneously, while crystals with other domain configurations demonstrate much lower k31. The analysis reveals that greatly enhanced electromechanical coupling can be obtained in domain-engineered ferroelectric crystals, and offers insight on the design and optimization of ferroelectrics for enhanced functional properties.