The opioid receptor system plays a major role in the regulation of mood, reward, and pain. The opioid receptors therefore make attractive targets for the treatment of many different conditions, including pain, depression, and addiction. However, stimulation or blockade of any one opioid receptor type often leads to on-target adverse effects that limit the clinical utility of a selective opioid agonist or antagonist. Literature precedent suggests that the opioid receptors do not act in isolation and that interactions among the opioid receptors and between the opioid receptors and other proteins may produce clinically useful targets. Multifunctional ligands have the potential to elicit desired outcomes with reduced adverse effects by allowing for the activation of specific receptor conformations and/or signaling pathways promoted as a result of receptor oligomerization or crosstalk. In this chapter, we describe several classes of multifunctional ligands that interact with at least one opioid receptor. These ligands have been designed for biochemical exploration and the treatment of a wide variety of conditions, including multiple kinds of pain, depression, anxiety, addiction, and gastrointestinal disorders. The structures, pharmacological utility, and therapeutic drawbacks of these classes of ligands are discussed.