Low level marijuana drug dealer David Clark is robbed of his money and stash, some of which he owes to his supplier. His boss, wealthy drug lord Brad Gurdlinger forces David to smuggle marijuana from Mexico in order to clear his debt. Realizing that one man attempting to get through customs is too suspicious, he hires a stripper stage-named Rose, a runaway 21 year old girl, petty thief named Casey, and his 18 year-old neighbor Kenny to pose as a bogus family called the "Millers". When the Millers reach the compound, they find out that the amount of marijuana they were picking up is not "a smidge" as Gurdlinger had informed them, but actually two tons. Because of the extra load of the marijuana on the RV, one of the radiator hoses breaks while going up a steep incline. A family they had encountered at the border called the Fitzgeralds, consisting of Don, Edith, and Melissa, catch up to them and tow the Millers' RV to a repair shop. On the trip to the shop, David learns that Don Fitzgerald is a DEA agent after finding his badge and gun in the glove compartment.
The marijuana turns out to be stolen from Pablo Chacon's cartel. The next day, when the Millers head to the shop to pick up the RV, Chacon and his henchman One Eye are waiting for them and prepare to execute the family. They immediately tell Chacon that they aren't a real family and that they didn't know they were stealing from him. Rose is given a chance to prove that she is a stripper by dancing, and when she gets close, turns a steam vent onto Chacon. The Millers then escape in the RV, with Kenny behind the wheel. Due to Kenny's erratic driving, the RV veers off the highway and a tarantula, hiding in a bowl of fruit given to them when they picked up the marijuana, crawls up Kenny's leg and bites his testicle. As Kenny has a severe allergic reaction to the bite, the Millers head to the hospital. This further delays the delivery of the contraband, but David re-negotiates with Gurdlinger for a fee of $500,000 on the condition that it arrives that night. When Kenny is finally released, David rushes him to the RV in a wheelchair and tips him over. In the ensuing argument, David inadvertently reveals how much he is getting paid, in comparison to how little he offered to pay each of the others. Casey, Rose, and Kenny are left in disgust by the revelation, and so David leaves them at the local carnival.
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