Polyamine toxins, isolated from spiders and wasps, have been used as pharmacological tools for the study of ionotropic receptors, but their use have so far been hampered by their lack of selectivity. In this mini-review, we describe how careful synthetic modification of native polyamine toxins have led to highly selective and potent new ligands for specific ionotropic receptors, particularly certain glutamate receptors subtypes, as well as nicotinic acetylcholine receptors. Moreover, the recent developments of synthetic methods, that have greatly facilitated the synthesis of polyamine toxins and their analogues are described.