Pat the shrimp dry with paper towels.
In a large bowl, mix the buttermilk and Cajun seasoning. Add the shrimp, cover and let stand for at least 30 minutes, or up to 1 hour.
In a shallow pie plate or bowl, mix the flour, salt, pepper, paprika, and garlic powder, until thoroughly combined
Prepare two baking sheets by placing a cooling rack on top of each; one for the uncooked coated shrimp, and the other to drain the shrimp after frying.
Add enough oil to a large heavy Dutch oven to measure 2½ to 3 inches, about 1 to 2 quarts of oil. Using a deep-fry thermometer, heat the oil to 375°F over medium high heat.
While the oil is heating, dredge the shrimp in the seasoned flour mixture, by draining off excess buttermilk and coating the shrimp evenly with the flour mixture. Place the coated shrimp on one rack on a baking sheet. (Having all the shrimp coated before frying allows for a quicker workflow.)
Fry the shrimp in batches in the hot oil until golden brown, 1 to 2 minutes, or until cooked through. Carefully remove the shrimp with a large slotted spoon or spider utensil, letting the excess oil drip back into the pot.
Drain the shrimp briefly on the other rack set over a baking sheet. Serve hot, with cocktail sauce for dipping, and lemon wedges