Solution-phase synthesis was the first developed and the only method for peptide synthesis until the solid phase peptide synthesis (SPPS) introduced by Merrifield revolutionized the way peptides and their analogs are prepared nowadays. However, some peptides because of their chemical structure cannot be synthesized by SPPS and the “old school” technique is still favorable to make them. Biphalin is a good example. It was first synthesized by Lipkowski 40 years ago as a dimeric analog of enkephalin in which two tetra-amino acid fragments (Tyr-D-Ala-Gly-Phe-) are joined tail to tail by a hydrazide bridge. The synthesis of this octapeptide (Tyr-D-Ala-Gly-Phe-NH-NH<-Phe<-Gly<-D-Ala<-Tyr) and its analogs requires synthesis in solution because routine synthesis on a polymeric support is not possible. Biphalin shows high affinity at both μ and δ opioid receptors and produces a more robust spinal analgesia than morphine after intrathecal administration. Although biphalin and its analogs have been already deeply investigated, a complete description of its analgesic activity is not yet available. Due to the continued interest of pharmacologists, biphalin is currently commercially available. Here, we present a detailed procedure for the solution phase synthesis of biphalin.