Agnes launched her second studio album, Whaddup A.. '?!, on 10 December 2005. It featured five singles: "Bukan Milikmu Lagi", "Tanpa Kekasihku", "Tak Ada Logika", "Cinta Di Ujung Jalan", and "Tak Mungkin". In addition to working with Indonesian musicians such as Melly Goeslaw, Andi Rianto, and Erwin Gutawa, she also collaborated with American singer-songwriter Keith Martin. Martin wrote two English songs for the album, including the duet "I'll Light a Candle". To promote the album, Agnes held a concert tour known as Clasnezenzation in four Indonesian cities: Bandar Lampung, Surabaya, Bandung, and Makassar. The album was commercially successful and she won two 2006 Anugerah Musik Indonesia awards for "Best Female Pop Artist" and "Best R&B Production". She also won the "Most Favorite Female" award at the 2006 MTV Indonesia Awards. She was nominated for "Favorite Indonesian Artist" award at the MTV Asia Awards 2005 (beaten by Peterpan) but, she grabs the youngest artist of all nominees in Asian category. Selling more than 450,000 copies, the album was one of the top-selling albums of 2006 and was certified triple platinum.
In 2005, Agnes appeared in the Taiwanese drama The Hospital, co-starring with Jerry Yan, a member of the Taiwanese boyband F4.She also appeared with Peter Ho in several episodes of the Taiwanese drama Romance in the White House, and starred in two Indonesian soap operas, Ku Tlah Jatuh Cinta and Pink, both televised on Indosiar. In 2006, she starred in the RCTI soap operaKawin Muda. She also decided to take a break from her education that year to focus on her entertainment career.
In early 2007, Agnes was appointed by the United States of America's Drug Enforcement Administration (DEA) and the International Drug Enforcement Conference (IDEC) Far East Region as an Asian anti-drug ambassador. On 15 May 2007, she was an opening act for American R&B group Boyz II Men at a concert in Istora Senayan, Jakarta, and on 23 June of that year, she held her first concert at Stadium Negara in Kuala Lumpur, Malaysia. She also guest starred in the finale of Asian Idol on 16 December 2007, and performed the song "Get Up".