When Realtor Sandra visits a foreclosed property with her client, the former owner Danny attacks them.

The notorious Gecko Brothers, two of America's most dangerous criminals, are on the run from the Texas police and the FBI after a crime spree through the Southwest. Across the border in Mexico, the mysterious Carlos offers sanctuary to criminals on the lam, but first they must slip past the border patrol. Enter the Fuller family: Jacob, a minister who has lost his faith and his children, the vulnerable teenage Kate and her younger brother Scott, on a road trip in their new R.V. The Gecko Brothers kidnap the Fullers and high-tail it to freedom with the promise to let the family go once they hook up with their criminal connection in Mexico. The rendezvous point is the Titty Twister, the wildest bar this side of the Rio Grande. The night is full of seductive promise as the group settles back to wait for Carlos and his boys to arrive at sunrise. But unbeknownst to the brothers or their hostages, the management and staff of this particular establishment have a taste for blood--in the vampire sense.

Two pretty American girls are on a road trip through Europe. In Germany they end up alone at night with a broken car in the woods. They search for help and find an isolated villa. The next day they awake to find themselves trapped in his terrifying makeshift basement hospital along with a Japanese man. An older German man identifies himself as a retired surgeon specialized in separating Siamese twins. However his three "patients" are not about to be separated, but joined together in a horrific operation. He plans to be the first person to connect people via their gastric system, in doing so bringing to life his sick lifetime fantasy "the human centipede".

Three friends accidently hit and kill someone while they are driving drunk. They opt not to tell anyone about the murder and, in time, they pretend to forget about it. Their crime comes back to haunt them the following summer when they each start receiving mysterious letters from someone who knows what they've done.