Introduction: Sickle cell disease (SCD) dramatically affects the wellbeing of patients by leading to disabilities, poor quality-of-life and reduced life expectancy. The morbidity and chronic nature of the disease inevitably affect the psyche and behavior of both patients and their families. Objective: To review the existing literature in order to highlight the psychosocial areas which are mainly affected by SCD with respect to the patients, the cohesion and functionality of their families and the interpersonal relations between family members. Materials and Methods: Both original research and review papers published in the last 30 years were searched within the PubMed database with particular emphasis on publications since 2000. The term SCD was combined with the following key words: coping, psychosocial problems, depression, and psychological problems. Selection of articles was based on representativeness and methodological adequacy. Results: High rates of anxiety, depression, behavioral problems and difficulties in interpersonal relationships are observed in SCD patients. SCD also affects family function and coherence. A well built social welfare system (network) can play a protective role. Despite the extensive documentation of psychological problems in patients with SCD, proper emphasis on prevention, etiological and holistic treatment and shielding of these families is lacking in daily clinical practice. Conclusions: The therapeutic approach of patients with SCD should always include the timely identification of dysfunctions in both children and their families and attempt to reduce the disproportionate burden that they are forced to withstand.