The design of macromolecules able to generate a stable binding with nucleic acids is of great interest for their possible application in gene delivery. During the last years particular attention has been addressed to the use of dendritic scaffolds as a base to construct efficient DNA and siRNA nano-carriers. Dendrimers and dendrons are hyperbranched polymers characterized by a well-defined structure and by the possibility to functionalize their surface in many different ways. In particular, their multivalent character allows the creation of multiple binding sites between the positively charged groups that decorate the surface of cationic dendrons and dendrimers and the negatively charged phosphate groups present on the strands of DNA and siRNA. The engineering of “ideal dendritic candidates” to deliver and release genetic materials into cells is, however, not trivial due to the huge distance that exists between the design phase and the real application of such molecules. A differentarchitecture of the dendritic scaffold (flexible or rigid) can strongly modify the binding efficiency, but, at the same time, is influenced by the interactions with the external solution. In this context, molecular simulation can represent a “virtual bridge” between the design and the comprehension of the real behavior of such macromolecules.