Abstract: As the representative supramolecular macrocycles of third generation, calixarene has the advantages of simple synthesis, easy functional modification and adjustable cavity size. The noncovalent interactions of host and guest exhibited several advantages in improving solubility of hydrophobic drugs, improving bioavailability, and decreasing toxicity or irritation. The characteristics of molecular assembly supply the calixarene with the ability to form different nano aggregates, which provides a new idea for drug delivery. Based on the two core functions of supramolecular macrocycles, host guest complexation and molecular assembly, the review elaborates on the research progress of water-soluble calixarene-based drug delivery system with nano structures and the applications, et al, in improving the solubility, increasing the bioavailability and targeting of antitumor drugs, reducing the rate of adverse reaction, et al, in recent 10 years.