Small interfering RNAs (siRNAs) are an attractive new agent with potential as a therapeutic tool because of its ability to inhibit specific genes for many conditions, including viral infections and cancers. However, despite this potential, many challenges remain, including off-target effects, difficulties with delivery, immune responses, and toxicity. Traditional genetic vectors do not guarantee that siRNAs will silence genes in vivo. Rational design strategies, such as chemical modification, viral vectors, and non-viral vectors, including cationic liposomes, polymers, nanocarriers, and bioconjugated siRNAs, provide important opportunities to overcome these challenges. We summarize the results of research into vector delivery of siRNAs as a therapeutic agent from their design to clinical trials in ophthalmic diseases, cancers, respiratory diseases, and liver virus infections. Finally, we discuss the current state of siRNA delivery methods and the need for greater understanding of the requirements.