Pharmacological management of severe and chronic pain remains a difficult achievement with currently available analgesic drugs. The design and development of potent opioid analogs with reduced tolerance, dependence, respiratory depression, and other unwanted side effects, could be of great value in the clinical treatment of chronic pain. The hierarchical approach to peptidomimetic design has dramatically advanced over the past three decades; a significant target in research since the discovery of multiple opioid receptors has been to develop highly potent and selective opioid receptor peptidomimetics that overcome the problems related to scarce bioavailability, enzymatic degradation, and low safety profile of natural peptides. Peptide drug design is a high multidisciplinary area that often relies on the state-of-the-art of organic chemistry, pharmacology, and biochemistry, computational methods and biophysical methods for determining the structural, conformational, topographical, and dynamic properties of designed ligands. With the aim to explore the recent advancements in opioids research, in this chapter, particular attention has been paid on the structural modifications of natural opioid peptides to obtain potent, selective, and stable opioid agonists. In addition, we focused our attention on μ/δ mixed agonists and novel approaches based on multitarget ligands, as discussed in section "Future Perspectives and Conclusions."