The increasing demand of synthetic oligonucleotides for therapeutic and diagnostic purposes can be hardly satisfied by simply up-scaling the commercial synthesizers. The introduction of a liquid-phase method that utilizes a polymeric support soluble into the reaction media can overcome the shortcomings related to the heterogeneity of the solid phase and allow a convenient large-scale process. Recently we have proposed a new synthetic approach for the oligonucleotide production that utilizes polyethylene glycol or PEG as soluble supporting polymer. We call this method High-Efficiency Liquid Phase or HELP. This approach preserves the advantages of a homogeneous synthesis in solution and adds an easy purification step of all the intermediates, mimicking the solid-phase procedure. In fact, reagent excess and byproducts can be eliminated by a simple precipitation-and-filtration step at the end of each synthetic cycle. Since all the reactions take place in solution, the scale-up of the process is easily predictable. Various synthetic protocols have been tested and optimized for the oligonucleotide production, up to the antisense-size level. After the phosphotriester and the phosphoramidite chemistry, the H-phosphonate approach is now under development. The possibility of an efficient automation of the whole process is also investigated.