Nasal absorption of insulin was discussed to develop a delivery system that targets the systemic circulation or central nervous system. Formation of insulin dimer and hexamer affects not only the diffusivity but also the membrane permeability of insulin via aqueous channels. The Renkin function was used to evaluate penetration pathways of hydrophilic compounds containing insulin through aqueous channels, and pore size and occupancy of the pathways were obtained as the membrane parameters on the basis of the function. Cationic polymers applied on the mucosal membranes as penetration enhancers increased the number of pathways for the hydrophilic compounds in the tight junctions, which suggested that these compounds could be sufficient as additives for the nasal delivery of insulin. However, excess interaction of the cationic enhancers with anionic insulin suppressed insulin permeation, and protection of insulin against degradation in the permeation process was required to improve the nasal absorption. PEGylation of insulin could be a possible way to improve the nasal delivery of insulin. In addition, combination of PEGylated insulin and modified cyclodextrin, which form pseudorotaxanes, can be applicable for further modification of pharmacokinetic and pharmacodynamic properties of insulin. Such well-designed complex systems may be required for specific delivery of insulin to the central nervous system.