In early 2000s, Del Castillo played the leading roles in telenovelas "Ramona" (2000), "El derecho de nacer" (2001) and "Bajo la misma piel" (2003-2004). In 2003, she made her American television debut playing a recurring role in the PBS comedy series "American Family" starring Edward James Olmos and Sônia Braga. In 2009, she had a recurring role in the Showtime dark comedy-drama "Weeds" playing Pilar Zuazo, a powerful woman in Mexican politics. In 2002 and 2003, she embarked on an international tour alongside Argentine actor Saul Lisazo with the play "Cartas de Amor" ("Love Letters"). In 2005, she starred alongside Demián Bichir in the romantic comedy film "American Visa". In 2006, Del Castillo starred in the film "Bordertown", which became her first role in Hollywood. In 2007, she went to star in the drama film "Under the Same Moon" directed by Patricia Riggen. The film grossed $23.3 million against $1.7 million budget. She also starred in a number of independent movies, include "The Black Pimpernel" (2007) and "Julia" alongside Tilda Swinton.