Neoplastic transformation is a consequence of maladaptive alterations in the cellular processes normally involved in cell growth, proliferation, differentiation, and survival. Despite the relative infrequent nature of skeletal neoplasms, current understanding of the pathobiology underlying these conditions is becoming increasingly characterized. This article highlights some of the established molecular abnormalities identified in various benign and malignant skeletal neoplasms and how they pertain to tumor biology, diagnosis, and prognosis. Most of the commonly accepted cellular aberrancies in skeletal neoplasms pertain to mutations, copy number changes, and/or chromosomal rearrangements. However, it is becoming increasingly understood that the complexity of tumorigenic pathways necessary for neoplastic growth are manipulated by numerous overlapping alterations in the genetic code and are further influenced by higher-order molecular programs, such as pretranscriptional and posttranscriptional regulation and chromatin reorganization. Over time, identification and quantification of these increasingly recognized neoplastic processes will gradually translate into valuable clinical applications, enhancing the current diagnostic and prognostic capabilities.