CB1 receptor (CB1R) antagonists were among the most promising molecules of pharmacological research in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems, however, use of rimonabant, the first marketed CB1R antagonist, has been suspended due to its anxiogenic and depressive side effects with potential suicide risk. The development of several other CB1R antagonists, like otenabant, surinabant and taranabant, all of them already in clinical trials, were interrupted. Since almost all other antiobesity drugs, like dexfenfluramine or sibutramine which act through other mechanism of action were also suspended earlier, the unmet need for drugs that reduce body weight became enormous. The possibilities of the safe use of CB1R antagonists including also further developments will be presented here. One approach is the use of CB1R antagonists that poorly cross the blood brain barrier. These compounds do not affect behavioural responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but do cause improvements in glucose homeostasis, fatty liver, and plasma lipid profile without sustained reduction in body weight (Tam et al, J Clin Investigation, 2010). The other approach is to use personalized medicine, namely genomics, to identify individuals who may benefit from treatment with centrally acting CB1R without psychiatric side effects (Lazary et al, Trends Pharmacol Sci in press, doi: 10.1016/j.tips.2011.02.013)