The integration of multiple imaging modalities in the assessment of musculoskeletal neoplasia is complex. Although no two instances are identical, certain guidelines can be gleaned from our experience as well as that reported in the literature. Assessment of most soft tissue masses is best carried forth with a combination of conventional radiography and magnetic resonance imaging (MRI). Screening skeletal scintigraphy without localizing symptomatology that includes axial and appendicular skeleton is best carried out initially with bone scintigraphy. Screening the axial skeleton in the presence of clinical symptomatology or a strong suspicion of axial skeletal metastases or pathology is best implemented as a total spine screening examination with MRI and specialized pulsing sequences. Computed tomography is reserved primarily for assessment of cortical and juxtacortical lesions, fracture fragment positioning and/or configuration, and characterization of lesion matrix calcification or ossification when conventional radiographs are indeterminate. Although physical examination and conventional radiography still remain the initial medical algorithms used to evaluate possible musculoskeletal neoplasia, primary skeletal tumors may require multimodality imaging to segregate aggressive and nonaggressive processes. In this multimodality scenario, bone scintigraphy has a critical role in assisting with differentiation between malignant and benign neoplasms.