The use of oligonucleotides (ONs) for gene therapy of certain diseases has been discussed since the late 1970s. ONs are single stranded chains of nucleic acids that can hybridize with target nucleic acid sequences to inhibit specific proteins, and therefore allow selective treatment of various diseases. The use of ONs is limited due to their instability in biological tissues and difficulty in delivery to the intracellular compartments of the cell. Chemical analog approaches have been used to address the instability issue and delivery systems have been developed to increase cellular uptake of ONs. It is generally thought that ONs with or without a delivery system are transported into cells by endocytosis, and then accumulate within endosomes where they are significantly inactivated. The rate and extent of movement of ON from endosomes appears to be important in determining ON effects. Consequently, developing accessory compounds or delivery methods that enhance endosome to cytoplasm transfer may be vital to ON therapy. This review focuses on investigating mechanisms of various delivery approaches at the cellular/intracellular level that have demonstrated utility in increasing ON activity or cellular accumulation. The future prospects of ON delivery are also addressed.