Since Ukraine gained independence, Kostyantyn Gryshchenko has served in a succession of senior positions with responsibilities ranging from arms control and regional security to education and public health.

1995–1998 –Deputy Minister of Foreign Affairs of Ukraine [9] with responsibilities covering arms control and disarmament, European security, the Commonwealth of Independent States, Russian Federation, Middle East, Asia, Africa and the Pacific region.

He played a key role in negotiating a number of crucial international agreements aimed at strengthening the independence, territorial integrity and security of Ukraine.

During this time Kostyantyn Gryshchenko initiated a large scale program for professional diplomatic training for newly recruited MFA personnel in a number of the EU countries and in the United States.

[13] During the Ukrainian-Russian Tuzla crisis in 2003 he engaged all diplomatic tools at his disposal to counter Moscow's attempts to challenge Ukraine's territorial integrity and return to normal relations with Russian Federation.

With deepening political crisis in the Ukrainian-Russian relations President Victor Yushchenko in April 2008 appointed Kostyantyn Gryshchenko First Deputy Secretary of Ukraine's National Security and Defense Council(NSDC)[16] and in July – Ambassador to the Russian Federation.

[17] Kostyantyn Gryshchenko continued serving as First Deputy Secretary of the NSDC giving Ukraine's Ambassador to Russia a special status that signaled the concern of the senior leadership over Ukrainian-Russian relations.

[18] During a TV duel with Dmitry Rogozin (then Russian Ambassador to NATO) Kostyantyn Gryshchenko stated that in Russia unacceptable ideology for developing normal Ukrainian-Russian relations is being imposed on society.

Under Kostyantyn Gryshchenko's guidance Ukrainian diplomats managed to negotiate visa free travel regimes with Israel,[21] Turkey,[22] Brazil,[23] Argentina.

Priority attention was paid to improve availability of medical care (development of a network of institutions of primary link and reforming system of emergency medicine), as well as adoption of the draft of Nationwide target social program of counteraction to HIV/AIDS for 2014–2018.

[28] As Vice Prime Minister, though not directly responsible for foreign policy, Kostyantyn Gryshchenko was on a number of occasions called upon to help Ukrainian citizens in distress.