Oral administration is widely accepted drug delivery system however, its use is limited due to physico-chemical properties of the drug such as poor solubility, low permeability, instability, and rapid metabolism as all of which decrease oral bioavailability. The low oral bioavailability of most drugs is still a major obstacle which creates challenges for pharmaceutical manufacturers to design drug delivery system with improved pharmacokinetics profile and therapeutic responses. The fundamental problem over the years has been to develop techniques that will allow most medications, regardless of their properties, to be administered orally in order to attain systemic availability. Many techniques have been explored to increase the water solubility of poorly water-soluble drug and thus their bioavailability. Cubosomes are novel lipid-based nano-system that are similar to well-known vesicular systems such as liposomes and niosomes. Cubosomes have been widely formulated in the presence of a suitable stabilizer using certain amphiphilic lipids (e.g., glyceryl monooleate and phytantriol). They could represent a novel drug delivery system containing hydrophilic, lipophilic, and amphiphilic drug molecules. They are widely used in a variety of drug delivery applications, including oral, ocular, transdermal, and chemotherapy drug delivery. In this review, cubosomes, their composition, methods of preparation and oral drug delivery applications will be critically reviewed.