As mentioned in the previous section, protamine is the only clinically approved agent to be employed in heparin anticoagulant activity reversal during chirurgical and medical practices. Derived from shellfish, this small arginine-rich cationic protein causes adverse reactions in nearly 10% of patients, and up to 2.6% of cardiac surgeries experience serious complications due to protamine suboptimal administration [30]. Since covalent dendrimers can mimic many aspects of protein behavior [31], we reasoned that these hyperbranched molecules, and particularly the poly(amidoamine) (aka PAMAM) dendrimers originally reported by Don Tomalia in 1985 [32], which feature positively charged groups on their outer surface, could work well as heparin ligands. Thus, we began our journey in the quest of possible protamine replacers by studying heparin binding by ethylenediamine (EDA)-core PAMAMs with different branching generations (G0–G6) by means of a combined experimental/computational approach [33].