Drug abuse is a major threat to public health (Compton et al., 2007; Gustavsson et al., 2011). For 40 years, NIDA has supported extensive research towards understanding molecular bases of drug abuse (Everitt et al., 2008; Nestler, 2005; Pierce and Wolf, 2013), and developing innovative strategies for treatment (Heilig et al., 2011; Kalivas and Volkow, 2011; Koob et al., 2009; Pierce et al., 2012; Volkow and Skolnick, 2012). We are extremely grateful to NIDA for long-standing support to our efforts in developing genetic mouse models for opioid research. Knockout (KO) mice for the opioid system, developed by others and us, have been extensively studied and broadly shared within our research community. In this review, we have gathered data from these KO mice that have accumulated in the past fifteen years (for previous reviews see (Contet et al., 2004; Kieffer and Gaveriaux-Ruff, 2002), and enabled identification or clarification of the specific role of each component of the opioid system in drug reward and addiction. Note that the opioid system plays a central role in pain processing, but this particular aspect will not be reviewed here (see recent reviews in (Bodnar, 2012; Gaveriaux-Ruff and Kieffer, 2011; Woolf, 2011).
