Highly substituted benzenes — like the penta- or hexasubstituted benzene cores of the illudalane sesquiterpenes — are underrepresented in medicinal chemistry and present long-standing challenges to chemical synthesis. Traditional synthetic approaches feature serial aromatic substitution, which becomes increasingly cumbersome with increasing substitution, rendering many substituted benzenes inaccessible for comprehensive pharmacological assessment. Despite these challenges, interest in the illudalanes and related compounds has surged in recent years, highlighted by the discovery that illudalic acid (from the toxic jack o’lantern mushroom Omphalotus illudens) is a potent and selective inhibitor of the LAR family of protein tyrosine phosphatases (PTPs). We will describe benzannulation methodologies and convergent syntheses of illudalic acid and illudalane-type structures aimed at advancing the pharmacology of drug abuse, including LAR/PTPRD inhibitors of interest for addiction research and a novel CB₂-selective indole cannabinoid antagonist.