Leukemia is the most common childhood malignancy, and it is often characterized by pallor, fatigue, cytopenia, and organomegaly; sometimes musculoskeletal symptoms, mainly characterized by diffuse bone pain in the lower extremities, are the onset clinical characteristics of the disease. In these cases, the disease may initially be misdiagnosed as reactive arthritis, osteomyelitis, or juvenile idiopathic arthritis delaying appropriate diagnosis and management. Even if leukopenia, thrombocytopenia, and a history of nighttime pain are reported to be the most important predictive factors for a pediatric leukemia, blood examinations can sometimes be subtle or within normal limits, and this represents a further diagnostic difficulty. Radiological findings of leukemic bone involvement are described in patients with musculoskeletal symptoms of acute lymphoblastic leukemia and often appear before hematologic anomalies, but they are not specific for the disease. However, they could be helpful to get the right diagnosis if integrated with other features; thus, it is important knowing them, and it is mandatory for the multidisciplinary comparison to talk about dubious cases even in an emergency setting. We describe 4 patients visited in the emergency department for musculoskeletal complaints and having radiological lesions and a final diagnosis of acute lymphoblastic leukemia, in whom the onset of the manifestations could mimic orthopedic/rheumatologic diseases.