Introduction Cannabis is one of the most commonly used illegal drugs worldwide. Cannabis use has been frequently associated with major affective disorders, and suicidal behavior. Objective We aimed to critically review the current literature concerning the possible association between cannabis use, major affective disorders and suicidal behavior. Early warning signs of affective conditions and suicidality in young adolescents who were cannabis users have been investigated providing a rationale for the importance of their early detection and assessment. Methods We performed a detailed Pubmed/Medline, and ScienceDirect search to identify all papers and book chapters focusing on the association between cannabis use, major affective disorders, and suicidal behavior during the period between 1980 and 2013. Results Early warning signs of emerging affective disorders include behavioral, emotional and cognitive abnormalities. Hopelessness may be considered as a specific risk factor of negative outcome and suicidal behavior among depressed individuals with a history of early cannabis use. Vulnerable subgroups of individuals include those who were heavy users of cannabis during adolescence, and those with past suicidal attempts or current hopelessness. Socio-demographic, parental and individual risk factors for both suicide risk and early cannabis are discussed. Overall, cannabis use may be considered a risk factor for developing both psychiatric disorders and suicidal behavior. Conclusions Preventive programs should be directed at reducing cannabis use among young adolescents, as well as at preventing/treating modifiable factors such as adolescent hopelessness. The active engagement of patients in the early phases of affective disturbances is crucial to prevent psychosocial impairment.