The largest fraction of global plant diversity is in the Neotropics, with the Atlantic Forest and the Amazon being examples of rich untapped reservoirs of species that may lead to new drug discovery. Bioactive molecules are often isolated from Rubiaceae species. Ethnobotanic and chemotaxonomic studies may provide clues to guide the prospection of bioactive molecules of interest. In South America, several genera are of special interest due to the bioactivities of their phytochemicals along with their importance to local human populations. Outstanding among these are Psychotria, Palicourea, Carapichea, Uncaria, and Cinchona. The numerous bioactivities of alkaloids from species in these genera include emetic, cytotoxic, analgesic, anxiolytic, antidepressant, psychotropic, antipsychotic, antipyretic, anti-inflammatory, antioxidant, antimutagenic, antitumoral, immunomodulatory, vasorelaxant, antiviral, antimicrobial, and antiprotozoal. Indole alkaloids are widely represented in these plant groups. Detailed studies in planta and in vitro on the dynamics of biosynthesis, accumulation, and distribution of these metabolites in some species of southern Brazil within these genera have revealed complex regulatory controls, encompassing responses to both developmental and environmental signals. In addition, even closely related alkaloids may present distinct dynamic profiles of accumulation, varying from constitutively produced to highly responsive to environmental signals.