During his time as chairman, he publicly endorsed Edmund Stoiber as the party's candidate to challenge incumbent Chancellor Gerhard Schröder in the 2002 federal elections.

On the Committee on Foreign Affairs, Wadephul was his parliamentary group's rapporteur on relations with the Middle East, Arab states of the Persian Gulf and Iran.

In the negotiations to form a coalition government under the leadership of Chancellor Angela Merkel following the 2017 federal elections, Wadephul was part of the working group on foreign policy, led by Ursula von der Leyen, Gerd Müller and Sigmar Gabriel.

He has since been serving as deputy chairman of the CDU/CSU parliamentary group under the leadership of successive chairs Volker Kauder (2017–2018), Ralph Brinkhaus (2018–2022) and Friedrich Merz (2022–present); in this capacity, he succeeded Franz Josef Jung.

[10][11] Ahead of the Christian Democrats' leadership election in 2021, Wadephul publicly endorsed Norbert Röttgen to succeed Annegret Kramp-Karrenbauer as the party's chair.

[13] In February 2025 Wadephul was called by the Russian comedy duo Vovan and Lexus, pretending to be employees of the Ukrainian president Volodymyr Zelenskyy.