Pentaerythritol and its congeners, such as pentaerythrityltetramine, 2,2-bis(aminomethyl)propane-1,3- diol, bis(hydroxymethyl)malonic acid, bis(aminomethyl)malonic acid and 2,2-bis(aminomethyl)-β-alanine, constitute an interesting class of tetrafunctional spiro compounds that allow the attachment of four different conjugate groups and, hence, the construction of highly branched and branched / cyclized structures. Accordingly, these compounds have received interest as orthogonally protected handles useful for the generation of combinatorial libraries and as building blocks that fit well in the general structure of oligonucleotides and peptides, providing additional functionalities for further derivatization. Another interesting feature is that 1,3-dicarbonyl spiro compounds and their analogues having an unprotected 2-(hydroxymethyl) group undergo a facile retroaldol condensation even under physiological conditions, although the compounds are entirely stable as long as the hydroxy function is masked with an acyl group. They have, hence, found applications as biodegradable protecting groups and linkers, the cleavage of which is triggered by intracellular esterases. The literature published on the synthesis of appropriately protected handles and building blocks from inexpensive starting materials, such as pentaerythritol or malonic esters, and their use in the synthesis of structural analogues and conjugates of oligonucleotides and peptides, glycoclusters and small molecule libraries is reviewed.