The CSIs arrive at a family residence where four people have been brutally stabbed. Mr. Collins is found in the second floor corridor, Mrs. Collins in her bed, and their two sons in their room.
Grissom questions Tina, the teenage daughter who escaped the massacre. He then talks to Brenda, the younger sister, but she does not say anything until Grissom asks if anyone went into her room. She quietly answers, "the buffalo" but does not say anything else. Grissom notes that a knife - presumably the murder weapon - is missing from the knife block in the kitchen
The CSIs discuss a possible sequence of events, speculating that the mother was killed first in her sleep and the father ran to protect his children, but was killed on the way to their rooms.
Brass and Grissom question Tina and learn that she has no boyfriend and does not know anyone called “Buffalo”. Grissom processes Tina’s clothing and finds no blood on them.
Sara is assigned to take care of Brenda, who shows signs of emotional shock and trauma. However, she breaks out of her catatonic state when she hears the word "buffalo", becoming hysterical and freaking out. Although Sara thinks that she is not good with children, Brenda attaches herself to her.
Outside, Nick and Warrick find a bidi and a match. They also find tire impressions which match a scooter owned by a boy in the neighborhood. He says that he does not know where his scooter is because he shares it with a few other boys and one of them has it.
Catherine and Grissom question Tina and remind her that she said she hugged her mother's body and tripped over her father's. Tina cannot explain why there is no blood on her pajamas.
The boys who share the scooter are questioned and Jesse Overton admits to having the scooter on the night of the murder but says he does not know where it is. During his interrogation he tries to light a bidi, and when Nick takes his cigarettes and his matches away he notices that two matches are missing from the book. Overton admits to having sex with Tina.
Tina asks Catherine and Grissom if she can see her sister, but is met with accusations that she caught her boyfriend killing her family. Nick matches the match found at the crime scene to Jesse's matchbook. Brass searches Jesse’s garage and finds the scooter and a pair of jeans covered in blood.
Jesse pleads guilty and takes a lie detector test. He admits to each killing and says that he killed them because Tina wanted to be with him and they wouldn't let her. The test shows that he was telling the truth that he had murdered them but lied when it came to the reason.
Grissom goes through the family's effects and finds an amulet on a chain which belonged to Mr. Collins. He cleans the blood off the amulet and discovers a buffalo. He immediately calls Sara and asks her to check Brenda for sexual abuse.
Catherine examines the photographs of the crime scene and tries to put together a timeline. She realizes that the evidence does not fit their theory that the killer killed the mother first and then killed the father as he tried to save his daughter. The blood drops actually indicate that the father was leaving Brenda’s room, and that the husband was killed first. The killer then went to the mother’s room, dropping blood on the floor from the knife.
Sara discovers that Brenda was being sexually abused, and Grissom and Brass interrogate Tina again. Tina reveals that she was also abused by her father and that Brenda is actually her daughter as well as her half-sister. She had her father killed to protect Brenda from the same abuse, and had her mother and brothers killed because they never tried to protect her.
Catherine receives a visit from social services and learns that her ex-husband Eddie filed a report saying she neglects her daughter Lindsey.
A similar plot structure, the murder of a family unit, was again written into a script in the season six episode: "Gum Drops". Nick investigates the murder and like this episode instead of blood being a major part of the case, it is gum, hence the title, "Gum Drops".