The Holy See (Vatican City) conducts an active diplomacy. As noted, it maintains formal diplomatic relations with 166 nations; 69 of these maintain permanent resident diplomatic missions accredited to the Holy See in Rome. The rest have missions located outside Italy with dual accreditation. The Holy See maintains 179 permanent diplomatic missions abroad.

The Holy See is especially active in international organizations. It has permanent observer status at the United Nations in New York, the Office of the United Nations in Geneva and specialized institutes, the UN Food and Agriculture Organization in Rome and the UN Educational, Scientific, and Cultural Organization in Paris. The Holy See also has a member delegate at the International Atomic Energy Agency and at the UN Industrial Development Organization in Vienna. It maintains permanent observers at the Organization of American States in Washington, DC, and the Council of Europe. In addition, the Holy See has diplomatic relations with the European Union in Brussels. In 1997 the Holy See became a member of the World Trade Organization.

In 1971, the Holy See announced the decision to adhere to the nuclear Non-Proliferation Treaty in order to "give its moral support to the principles that form the base of the treaty itself." The Holy See is also a participating state in the Organization for Security and Cooperation in Europe.

The Holy See is the only European state that still recognizes the Republic of China (on Taiwan) rather than the People's Republic of China. It is the longest lasting diplomatic ally of the ROC, having held official relations since 1942. Talks between the PRC and the Holy See on diplomatic recognition have been ongoing, with the main issue the treatment of Chinese Catholics. The PRC government maintains a Chinese Catholic Association which does not recognize the authority of Rome and has officially banned an underground Catholic Church which does recognize the Holy See's authority.

See also: Apostolic Nuncio