Morphine is a widely used opioid analgesic, but great individual differences in response to morphine such as sensitivity to analgesia and susceptibility to tolerance, which due to chronic morphine treatment, are great challenges for clinicians to optimize treatment strategy. Genetic factors play an important role in individual variability to morphine treatment. Individual responses to morphine are influenced by various gene-encoded-proteins implied in pharmacokinetics and pharmacodynamics. Variants of P-glycoprotein encoding gene ABCB1 regulate transportation and distribution of morphine and affect analgesic effect. Diversity in UDP-glucuronosyl transferase encoding gene UGT2B7, whose encoding product catalyzing morphine to glycosylated metabolites contribute to different response to morphine in a pharmacokinetic way. Nevertheless, variants in μ-opioid receptor encoding gene OPRM1 and catechol-O-methyltransferase encoding gene COMT regulate morphine-induced downstream signaling and influence morphine analgesia in a pharmacodynamic way. It is necessary to employ individuals with more complex genetic diversity and screen in a larger scope through a more comprehensive system to find the key genes involved in individual differences of morphine analgesia in future research. Elucidating the association between genetic variability and individual differences will help to figure out the mechanism of pharmacogenetic regulation in morphine analgesia. It will provide basis for personalized and accurate utility of morphine or even combining with gene therapy to improve the analgesic effect.