Gene therapy through the use of siRNA and a polymeric carrier are becoming an efficient therapeutic option to conventional pharmaceutical formulations for the treatment of deadly diseases, such as cancer, pulmonary, ocular and neurodegenerative diseases. However, several considerations regarding the stability, formulation, and efficacy have to be faced up until these systems could be considered to be a marketable pharmaceutical products for to extend siRNA application to clinical practice. This review is focused on the key challenges of siRNA therapeutics, with special attention on the faced obstacles and on the formulation-related difficulties, providing a list of requirements needed for obtaining an ideal carrier for siRNA. Moreover, the current non-viral polymers investigated for the realization of efficient carriers for siRNA are described, with a special attention on synthetic polyamines such as polyethylenimine (PEI), polysaccharides such as chitosan and inulin (INU), and polyaminoacids such as α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) and poly-l-lysine (PLL).