Publisher Summary Hypercalcemia is one of the most frequent paraneoplastic syndromes and often occurs in advanced stages of the disease. This chapter focuses on the parathyroid hormone-related peptide (PTHrP) and other systemic factors in skeletal manifestations, which are malignant. It begins with a description of molecular and cellular biology of PTHrP, taking into consideration, characteristics of the PTHrP gene and processing and degradation of PTHrP. Following this, it explains the mechanisms of action of PTHrP. The mechanisms include interaction of amino-terminal PTHrP with cell surface receptors, actions of carboxy-terminal PTHrP, and intracellular mechanism of PTHrP action. Furthermore, it describes the PTHrP actions on the bone, kidney, and tumor cells. It also establishes the relationship of PTHrP-producing tumors with the bone microenvironment. The other systemic mediators of malignancy (MAH) include cytokines, 1,25-Dihydroxyvitamin D (1,25(OH)2 D), and parathyroid hormone. Finally, this chapter describes some experimental approaches to controlling overproduction or over activity of PTHrP in MAH.