The endocannabinoid (ECB) system comprises cannabinoid receptors, ECBs and the whole machinery for the synthesis and degradation of ECBs. It has emerged as an important signalling system in the nervous system, controlling numerous physiological processes, including synaptic transmission, learning and memory, reward, feeding, neuroprotection, neuroinflammation, and neural development. This system is also implicated in various diseases of the nervous system, and thus has become a promising therapeutic target. The use of genetically modified mice has contributed crucially to our rapidly expanding knowledge of the ECB system. In this chapter, the existing mouse mutants targeting the ECB system will be discussed in detail. The use of conditional mutants has given an additional dimension to the analysis of the system, and, it is hoped, will finally enable us to understand this widespread and complex system in the context of intricate networks where different brain regions and neurotransmitter systems interact tightly with each other.