Peptide nucleic acids (PNAs) are attractive, as compared to other classes of oligonucleotides that have been developed to date, in that they are relatively easy to synthesize and modify, hybridize to DNA and RNA with high affinity and sequence selectivity, and are resistant to enzymatic degradation by proteases and nucleases; however, the downside is that they are only moderately soluble in aqueous solution. Herein we describe the protocols for synthesizing the second-generation γPNAs, both the monomers and oligomers, containing MiniPEG side chain with considerable improvements in water solubility, biocompatibility, and hybridization properties.