Resorcylates are a large group of bioactive natural products that are biosynthesized from acetate and malonate units via the intermediacy of polyketides. These polyketides undergo cyclization reactions to introduce the aromatic core. The bioactivities of the resorcylates including resorcylate macrocyclic lactones include anticancer, antimalarial, mycotoxicity, antifungal, and antibiotic properties, and several compounds in the series are already in use in medicine. Examples are prodrugs derived from mycophenolic acid as immunosuppressants and the Hsp-90 inhibitor, AT13387, which is in phase-II clinical trials for the treatment of small cell lung cancer and melanoma. In consequence of these biological activities, methods for the concise synthesis of diverse resorcylates are of considerable importance. In natural product chemistry, biomimetic total synthesis can have significant advantages including functional group tolerance in key steps, the minimization of the use of protection and deprotection reactions and the shortening of the total number of synthetic steps. This Account provides a description of our adaption of the dioxinone chemistry of Hyatt, Clemens, and Feldman for the synthesis and retro-Diels-Alder reactions of diketo-dioxinones. Such dioxinones, which were synthesized by a range of C-acylation reactions, were found to undergo retro-Diels-Alder reactions on heating to provide the corresponding triketo-ketenes with the loss of acetone. The ketene reactive intermediates were rapidly trapped both inter- and intramolecularly with alcohols to provide the corresponding β,δ,ζ-triketo-esters. These compounds, which consist of keto-enol mixtures, readily undergo cycloaromatization to produce resorcylate esters and macrocyclic lactones. We have established the use of diketo-dioxinones as key general intermediates for the synthesis of diverse resorcylate natural products and for the synthesis of new classes of compounds for the generation of medicinal chemistry lead structures. Many of the methods used were found to be tolerant of multiple sensitive functional groups. These include enolate C-acylations with acyl chlorides, 1-acyl-benzotriazoles, acyl imidazolides, or Weinreb amides to prepare diketo-dioxinones and their subsequent use to prepare β,δ,ζ-triketo-esters and lactones and hence resorcylates. In addition, in most cases, phenol protection was avoided. As an alternative to the synthesis of β,δ,ζ-triketo-esters, diketo-dioxinones were also found to undergo cycloaromatization with retention of the ketal entity via a nonketene pathway. Finally, diketo-dioxinones with an allyl, prenyl, geranyl, or other 2-alkenyl carboxylate esters at the γ-carbon underwent decarboxylative rearrangement with tetrakis(triphenylphosphine)palladium catalysis to produce α-substituted diketo-dioxinones and resorcylates with 3-allyl, prenyl, geranyl, or other 2-alkenyl groups. Such diketo-dioxinone chemistry was used in the total synthesis of natural products including aigialomycin, cruentaren A, and the oligomeric resorcylate antibiotics ent-W1278 A, B, and C. Additionally, tandem use of the decarboxylative rearrangement process and cycloaromatization was used in the total synthesis of natural products including the methyl ester of cristatic acid, mycophenolic acid, and hongoquercin B. The methodology was also applied to the synthesis of 9,10-anthraquinones, o-aminoalkyl resorcylates, dihydroxyisoindolinones, oligomers, and resorcinamides. The development of this methodology is described in this Account, showcasing its applicability and versatility for the synthesis of complex resorcylate products.