Ketones are fundamental synthons in organic synthesis due to their wide range of applications, which include natural products, pharmaceuticals, dyes, fragrances, agrochemicals, and electronic materials. In recent years, direct acylation strategies based on commercially available benchtop aryl halides and aldehydes (alkyl/aryl) have been the prime focus for the construction of alkyl-aryl/aryl-aryl ketones using palladium catalysis under eco-friendly reaction conditions. In this account, we present conceptually developed palladium-catalyzed direct acylation strategies for achieving various carbo- and heterocycles such as ketones, 2-quinolinones, phthalazines, phthalazinones, benzoxazinones, anthraquinones, indenones, and 1,3-dihydroisobenzofurans. Significantly, these direct acylation strategies have been extended to synthesize the natural product neo-lignan and biologically significant molecules such as an n-butylphthalide antiplatelet drug, pitofenone, fenofibrate, a HBV inhibitor, and a PDE-4 inhibitor. This Account will be of interest to synthetic organic chemists wishing to prepare pharmaceutical molecules and natural products.1 Introduction2 Discussion2.1 Palladium-Catalyzed Environmentally Compassionate Acylation2.2 Palladium-Catalyzed Acylations Followed by Intramolecular Aldol Condensation to Afford Indenones2.3 Acylation of Iodo-acetanilides/Iodo-phenyl Acetates: Sequential One-Pot Syntheses of 2-Quinolinones2.4 A One-Pot Diversified Synthesis of Phthalazines, Phthalazinones, and Benzoxazinones2.5 Palladium-Catalyzed Direct Acylation: A One-Pot Relay Synthesis of Anthraquinones2.6 Palladium-Catalyzed Direct Oxidative Coupling of Primary Alcohols with Iodoarenes Leading to Ketones: Application to the Synthesis of Benzofuranones and Indenones3 Conclusion