In January 2001, she was elected as vice-president of her political party, and in 2003 announced her candidacy as Senator for the Puerto Rico General Elections of 2004. On November 2, 2004, Santiago was elected, becoming the first woman to represent the Puerto Rican Independence Party in Puerto Rico's Senate.[4]
As a senator, Santiago has been involved in women's, mental health and special education issues, among others.[6]
Santiago is the writer of a column that is published in the El Vocero newspaper. She was arrested during the Navy-Vieques protests for illegally trespassing military facilities to protest the United States military's bombing practice in Vieques. She spent one month in jail as part of her sentence.[6]