This Account describes the development of a general method for the arylation of carbon-hydrogen (C-H) bonds using palladium and copper catalysts. The authors address three major challenges in C-H bond functionalization: substrate specificity, the conversion of unactivated sp³ C-H bonds to C-C bonds, and the high cost of palladium, rhodium, and ruthenium catalysts. They have developed a method for directing-group-containing arene arylation using aryl iodides and palladium acetate, which can be applied to anilides, benzamides, benzoic acids, benzylamines, and 2-substituted pyridine derivatives under similar conditions. Additionally, they have created a palladium-catalyzed auxiliary-assisted arylation method for unactivated sp³ C-H bonds, enabling β-arylation of carboxylic acid derivatives and γ-arylation of amine derivatives. The copper-catalyzed arylation of acidic arene C-H bonds (pKa < 35 in DMSO) is also described, allowing the arylated products to form at the most hindered position. This method complements C-H activation/borylation methodologies, which typically form functional groups at the least hindered position. The authors anticipate that other transition metals, such as iron, nickel, cobalt, and silver, can also facilitate deprotonation/arylation reactions.This Account describes the development of a general method for the arylation of carbon-hydrogen (C-H) bonds using palladium and copper catalysts. The authors address three major challenges in C-H bond functionalization: substrate specificity, the conversion of unactivated sp³ C-H bonds to C-C bonds, and the high cost of palladium, rhodium, and ruthenium catalysts. They have developed a method for directing-group-containing arene arylation using aryl iodides and palladium acetate, which can be applied to anilides, benzamides, benzoic acids, benzylamines, and 2-substituted pyridine derivatives under similar conditions. Additionally, they have created a palladium-catalyzed auxiliary-assisted arylation method for unactivated sp³ C-H bonds, enabling β-arylation of carboxylic acid derivatives and γ-arylation of amine derivatives. The copper-catalyzed arylation of acidic arene C-H bonds (pKa < 35 in DMSO) is also described, allowing the arylated products to form at the most hindered position. This method complements C-H activation/borylation methodologies, which typically form functional groups at the least hindered position. The authors anticipate that other transition metals, such as iron, nickel, cobalt, and silver, can also facilitate deprotonation/arylation reactions.