The structural design and additive manufacturing (AM) of cross-flow heat exchangers (HXs) are studied. A unit-based design framework is proposed to optimize the channel configuration in order to improve the heat exchange performance (HXP) and meanwhile control the pressure drop (PD) between the fluid inlet and outlet. A gradient-based optimization methodology is employed to drive the design process. Both shape and topology changes are observed during the channel configuration evolution. Moreover, AM printability evaluation is considered and some re-design work is proposed to improve the printability of the designs with respect to the metal laser powder bed fusion (LPBF) process. For an optimized structure from the unit-based design, corner rounding operation is adopted first, specifically to avoid sharp features. Then the building process of the entire HX containing top, bottom caps, side walls, and the optimized thin-walled channels is simulated, and residual deformation is predicted through sequential layer-by-layer analysis. Based on the residual deformation profile, geometrical compensation is implemented to reduce geometrical inaccuracy of the printed HX. In addition, build orientation selection is also studied to avoid overhang issues in some specific unit-based design results. Finally, a mature design scheme for the cross-flow HX can be achieved as the solution that leads to largely improved HXP (e.g., nearly 200% increase), well controlled PD, and enhanced printability with respect to the LPBF AM process.