Sickle cell disease (SCD) is the best known haemoglobinopathy, caused by a mutation substituting valina for glutamic acid at position 6 of the beta-globin chain of adult hemoglobin A, resulting in hemoglobin S (HbS). The homozygous HbS disease (HbSS), an autosomal recessive disorder, is the most common form and the Mediterranean area, along with sub-Saharian African and India, have the highest prevalence (1%-15%). In particular, Sicily with a prevalence of 2%-5%, is among the most interested regions. However, migratory flows have led to a wider diffusion of the disease no longer confined to endemic areas. In Europe, the yearly estimate of affected births are 1,300 but more than 90% of children with SCD survive into adulthood thanks to screening programs and early available care; however, their lifespan remains shortened by two or three decades compared to general population. In Greece, the number of affected births surpassing 100,000 yearly and the total number of newborns carrying two deleterious genes, if no prevention measures are taken, is estimated to be about 120-130/year. Diagnosis of SCD is based on analysis of haemoglobin through protein electrophoresis or chromatography, that are cheap and widely available techniques, even if haemoglobin mass spectrometry and DNA analysis are techniques with high-throughput testing. Prenatal diagnosis is used in many European countries, so the number of affected newborns has significantly decreased during the last 3 years. Over the course of SCD, sickling process may cause acute and chronic abdominal pain due to vaso-occlusive crisis, bone pain often in long bones due to bone marrow infarction, chronic hemolytic anemia, splenic sequestration with rapid enlargement of the spleen, delayed sexual maturation and cholelithiasis, with important inter-indivuidual variability. Sickle hepatopathy reflects liver sickling process within hepatic sinusoids and includes gallstone disease, hepatic sequestration, hepatic sideroris, acute sickle cell hepatic crises (ASHC) and sickle cell intrahepatic cholestasis (SCIC). Clinically, it appears with fever, right upper quadrant pain, jaundice and increased serum liver function tests. These patients are repeatedly esposed to trasfused red cells that contributes to iron overload and may contribute to hepatic haemosiderosis. Increased bone turnover and resorption by osteoclasts and by marrow expansion due to activation of hematopoiesis. The hematopoietic system may expand physiologically. Computed tomography (CT) is an easily reproducible imaging method that allows the morphologic whole-body evaluation although with a high dose of radiation exposure and possible side effects from intravenous contrast media. Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive technique without radiation chosen to image cholangiopathy and may be followed by the execution of endoscopic retrograde cholangiopancreatography (ERCP) in case of gallstone disease. Otherwise it can be helpful in identifying extramedullary hematopoiesis sites. Dual-energy X-rays absorptiometry (DEXA) is performed to evaluate deficit of bone mineral density (BMD), in which reduction of osteoblastic activity, high risk for necrosis may induce to fragility fractures. We recently had the experience of a typical case of a 56 years old Albanian woman with SCD, with jaundice after a long history of recurrent vaso-occlusive crisis. She was submitted to splenectomy and cholecystectomy 5 years before and since then she was treated with hydroxyurea. Hemocromatosis was excluded by genetic analysis. Hepatic biopsy (Pearl's stain) showed sinusoidal dilatation and diffuse iron accumulation in hepatocytes and Kupffer cells. Endo-hepatic jaundice was observed in MRCP images. It was interesting that DEXA examination was within normal range in both right proximal femur. This may probably be due to the presence of sclerotic lesions in the vertebrae, as was seen in the CT images. Technetium-99m-methylen bisphosphonate (Tc-MDP) skeletal scintigraphy is a higly sensitive whole-body diagnostic nuclear medicine technique able to evaluate early bone metabolic changes. Multimodality SPET/CT allows to correlate scintigraphic findings with anatomical images with higher sensitivity and specificity. The higher uptake of Tc-MDP in SCD patients is due to the activation of hematopoetic system and relies on the osteoblastic response to bone resorption as in our patient. The Tc-MDP scan may be better than fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) to show sclerotic lesions. Technetium-99m nanocolloids bone marrow scintigraphy (BMS) provides information about the assessment of the reticulum-endothelial system (RES), the whole-body distribution of functional red bone marrow and the presence and the extent of extramedullary hematopoiesis, especially in liver, spleen and bone marrow. Fluorine-18-FDG PET/CT completes the whole-body assessment with an integrated multimodal approach with high spatial resolution that evaluates the metabolic activity and the standardized uptake value (SUV) in SCD patients. Modern genetic diagnosis and gene treatment give promise for having fewer cases of SCD in the future.