So anyway the film starts off in the year 1937 in a secret underground government laboratory where tests are being performed on the effects of marijuana. Private Greg B. Miller (Bill Hader) is a subject in a test to decide if marijuana should be illegal. Miller, obviously high, begins to insult the government and his superiors. As a result, the government deems marijuana illegal and quickly "disposes of" Private Miller.
Jumping to the present day, Dale Denton (Rogen), a 25 year-old process serving stoner, visits his girlfriend Angie (Amber Heard) at her high school and argues about accepting an invitation to eat dinner with her family. Next, he visits his equally stoned dealer, Saul Silver (Franco), to buy bud. Saul offers him a rare and potent strain of marijuana called Pineapple Express alleged to be “the dopest dope [you]’ve ever smoked". After making his purchase, Dale agrees to smoke a 'cross-shaped' joint with Saul before leaving. He then leaves his apartment, smokes more, and ends up in front of the house of the next person he is supposed to serve, Ted Jones (Gary Cole), who Saul has mentioned as a drug lord.
While waiting outside in his car smoking a joint made of Pineapple Express, Dale witnesses Ted and a corrupt female police officer, Carol Brazier (Rosie Perez) commit murder. As Dale panics, he accidently throws his roach out the window and leaves the scene, while hitting two parked cars in the process (one being Carol's police cruiser). As Ted and Carol run outside to find Dale driving away, they determine that he saw the murder and are able to classify the roach he threw out the window as the rare Pineapple Express. Dale drives back to Saul's in a panic to ask Saul about Ted and eventually concludes that he could be traced back to Saul by the rare Pineapple Express (Saul is the only dealer who has it, and Ted is the only supplier). Dale and Saul leave the apartment. Meanwhile, Ted is determined to catch the witness of the murder so he dispatches two of his thugs, Matheson (Craig Robinson) and Budlofsky (Kevin Corrigan), so that they could find and dispose Dale and Saul. You can pretty much guess what happens when wasted guys and a pile of superweed end up chased by a druglord so im gonna stop the spoilers here.