Since their inception in the 1980s, oligonucleotide-based (ON-based) therapeutics have been recognized as powerful tools that can treat a broad spectrum of diseases. The discoveries of novel regulatory methods of gene expression with diverse mechanisms of action are still driving the development of novel ON-based therapeutics. Difficulties in the delivery of this class of therapeutics hinder their in vivo applications, which forces drug delivery systems to be a prerequisite for clinical translation. This review discusses the strategy of using lipid nanoparticles as carriers to deliver therapeutic ONs to target cells in vitro and in vivo. A discourse on how chemical and physical properties of the lipid materials could be utilized during formulation and the resulting effects on delivery efficiency constitutes the major part of this review.