The TV series tells the story of Rosario Tijeras (Maria Fernanda Yepez), a woman raised in a slum that was 18 years old when she was raped by a local gang, and which causes her to change for the better after her classmate was killed by a drug lord, El Papa. Rosario avenges her rape by cutting El Cache's testes with scissors (hence the name, Rosario Tijerias) and purposely goes to the market of her stepfather to get picked up to go to El Papa's house so she can execute her plan. Once Rosario is alone in his bedroom, she grabs a gun he hid in a cabinet and kills him behind a pillow. After news spreads she killed El Papa, Rosario Tijeras gains notoriety and is sought out by El Rey De Los Cielos (The King of the Heavens) to become an assassin. Along the way, she has a stormy love affair with her two inseparable friends from wealthy families, Antonio de Bedout (Andres Sandoval) and Emilio Echegaray (Sebastián Martínez).
The story takes a five year jump from 1999 to 2004, where Rosario meets Emilio at a nightclub after she killed a target. Antonio notices her for the first time in five years and seeks to be with her once again. Their lives are separated by Rosario, which traps them and takes them to a world full of dangers, where she is a victim and instrument of death and they receive a deadly fate thanks in part to a woman they loved before Rosario, Paula Restrepo, who seeks to destroy Rosario for ruining her love life and at the end she is left without her best friend and husband. Rosario pays the ultimate price when she kills the brother of El Rey, El Teo, who killed her brother (Jhonefe), her close friend (Ferney) who tried to kill her by Teo's orders, her unborn baby in a shootout, and Emilio at the cemetery. Rosario and Antonio plan their escape to Spain but are stopped short by El Rey's men who fulfill his orders and kill both. The series ends with Rosario having a makeshift memorial made near her old home where she lived.