Dale Denton (Seth Rogen), cuyo trabajo es entregar citaciones judiciales, le compra la marihuana a Saúl, un camello (James Franco) que le vende un nuevo tipo de hierba llamado “Pineapple Express”, en honor a un fenómeno atmosférico. Saul quiere hacerse amigo de Dale, pero a éste sólo le interesan los negocios. Casualmente, Dale es testigo de un asesinato cometido por una policía corrupta (Rosie Perez) y por el líder de una banda (Gary Cole). En un descuido se deja en la escena del crimen un poco de la hierba de Saúl. A partir de entonces ambos tendrán que huir tanto de la banda de criminales como de los agentes de la ley.
Sinopsis en inglés:
Lazy court-process clerk and stoner Dale Denton has only one reason to visit his equally lazy dealer Saul Silver: to purchase weed, specifically, a rare new strain called Pineapple Express. But when Dale becomes the only witness to a murder by a crooked cop and the city's most dangerous drug lord, he panics and dumps his roach of Pineapple Express at the scene. Dale now has another reason to visit Saul: to find out if the weed is so rare that it can be traced back to him--and it is. As Dale and Saul run for their lives, they quickly discover that they're not suffering from weed-fueled paranoia: incredibly, the bad guys really are hot on their trail and trying to figure out the fastest way to kill them both. All aboard the Pineapple Express.