<jats:title>Abstract</jats:title><jats:p>The kibdelones are a novel family of bioactive heterocyclic polyketides produced by a rare soil actinomycete, <jats:italic>Kibdelosporangium</jats:italic> sp. (MST‐108465). Complete relative stereostructures were assigned to kibdelones A–C (<jats:bold>1</jats:bold>–<jats:bold>3</jats:bold>), kibdelone B rhamnoside (<jats:bold>5</jats:bold>), 13‐oxokibdelone A (<jats:bold>7</jats:bold>), and 25‐methoxy‐24‐oxokibdelone C (<jats:bold>8</jats:bold>) on the basis of detailed spectroscopic analysis and chemical interconversion, as well as mechanistic and biosynthetic considerations. Under mild conditions, kibdelones B (<jats:bold>2</jats:bold>) and C (<jats:bold>3</jats:bold>) undergo a facile equilibration to kibdelones A–C (<jats:bold>1</jats:bold>–<jats:bold>3</jats:bold>), while kibdelone B rhamnoside (<jats:bold>5</jats:bold>) equilibrates to a mixture of kibdelone A–C rhamnosides (<jats:bold>4</jats:bold>–<jats:bold>6</jats:bold>). A plausible mechanism for this equilibration is proposed and involves air oxidation, quinone/hydroquinone redox transformations, and a choreographed sequence of keto/enol tautomerizations that aromatize ring C via a quinone methide intermediate. Kibdelones exhibit potent and selective cytotoxicity against a panel of human tumor cell lines and display significant antibacterial and nematocidal activity.