In this chapter, the neuroanatomical overlap in the distribution of orexin and endocannabinoid systems, as well as the functional interaction between leptindriven synaptic rewiring of orexinergic neurons and the orexin receptor-mediated activation of 2-arachidonoylglycerol synthesis, will be presented in the context of their role in the regulation of appetite, reward, sleep/wake, and analgesia. This chapter attempts to piece together what is known about this important cross talk and points out its potential therapeutic implications.