The prenyl diphosphate synthases, farnesyl diphosphate synthase (FDPS), and geranylgeranyl diphosphate synthase (GGDPS) are responsible for the production of two key isoprenoids farnesyl diphosphate (FPP) and geranylgeranyl disphosphate (GGPP). Not only do these isoprenoid diphosphates serve as precursors for other isoprenoids, but they are also the lipid donors for protein prenylation reactions. The nitrogenous bisphosphonates (NBPs) are inhibitors of FDPS and are widely used clinically in the management of a variety of bony disorders including osteoporosis and metastatic bone disease. The mechanism of action underlying their effects on osteoclasts appears to be predominantly related to their ability to diminish protein prenylation. Of increasing interest is the development of specific GGDPS inhibitors. Here, we discuss the use of FDPS and GGDPS inhibitors as an alternative strategy with which to impair protein prenylation and to disrupt isoprenoid homeostasis.