While our understanding of the neurobiological mechanisms underlying cocaine and opiate reward has historically been dopamine-focused, evidence from genetic and pharmacological approaches indicates that µ-opioid receptors (MORs) in the striatum are important contributors. Within the striatum, MORs are expressed in both dopamine D1-receptor and D2-receptor expressing GABAergic medium spiny neurons (MSNs), as well as in interneurons and various afferents. Thus, it remains unclear how these distinct MOR populations regulate drug reward. To address this, we generated mice with a targeted deletion of MORs from dopamine D2 receptor-expressing MSNs (D2-MORKO) and tested the locomotor and conditioned rewarding effects of cocaine and morphine. D2-MORKO mice showed blunted acquisition of cocaine place preference and suppressed expression of preference when tested in the presence of cocaine. Conversely, the acute and sensitized locomotor responses to cocaine and morphine, as well as morphine conditioned place preference, were normal in D2-MORKOs. This indicates MORs expressed in D2-MSNs facilitate cocaine reward. Further, these data suggest these MORs play divergent roles in cocaine and morphine reward.