Herein the evolution in the development of new sigma (sigma) receptor ligands since the middle '90s by our research group is reported. In the effort to contribute to the identification of the structural features for high-affinity ligands selective versus serotonin, dopamine and other CNS-related receptors, two general classes of (naphthalene)alkylamine compounds were prepared and explored, with the aim of addressing the affinities toward the two recognized sigma receptor subtypes. The common template of these compounds was mainly an unsubstituted or methoxy-substituted naphthalene or tetralin nucleus, linked by an alkyl spacer to a substituted piperazine or piperidine ring. The design of new ligands was thought keeping in mind their possible application as PET diagnostic tools and fluorescence tools. High-affinity sigma(2) receptor ligands were found among N-cyclohexylpiperazine derivatives, such as 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (3) (PB 28), when they were assayed in radioligand binding with [(3)H]-DTG in rat liver. Unfortunately, these ligands were all devoid of a significant selectivity relative to sigma(1) receptor whose binding was assayed with (+)-[(3)H]-pentazocine in guinea pig brain. Nevertheless, compound 3 had previously shown to be 40-fold selective with a slightly different binding method in animals' tissues. Moreover, it demonstrated 46-fold and 59-fold sigma(2) versus sigma(1) receptor binding selectivity in MCF7 and MCF7 ADR tumor cell lines respectively. In the class of piperazines, also high-affinity sigma(1) receptor ligands were found, possibly due to the presence of a double N-atom and an additional reverse mode of binding. Piperidine derivatives were investigated as high-affinity and selective sigma(1) receptor ligands leading to some 3,3-dimethylpiperidines such as 3,3-dimethyl-1-[3-(6-methoxynaphthalen-1-yl)propyl]piperidine (69) which resulted to be highly selective relative to the sigma(2) receptor. For the best ligands, functional assays were conducted in order to investigate agonist/antagonist activity. The effect of chirality in the intermediate methyl-alkyl chain was explored for a class of 4-methylpiperidines linked to some (4-chlorophenoxy)alkyl moieties, and compound (-)-(S)-92 emerged as the most selective sigma(1) relative to sigma(2) receptor ligand.