Clinical observations have revealed a strong correlation between loss of bone density in HIV-infected individuals, particularly in conjunction with the antiretroviral drug tenofovir, a nucleotide analog that inhibits HIV reverse transcriptase. The most compelling correlations have been observed in clinical studies involving young children and adolescents. These observations strongly suggest that bone density is being affected during active bone growth and development, implicating a role for tenofovir in bone loss. Here we discuss the literature and potential mechanisms for how tenofovir-associated bone loss may arise, which likely involves perturbation of cellular DNA synthesis and gene expression. Elucidation of the mechanism(s) involved in tenofovir-mediated bone loss will help in developing adjuvant therapies to reduce tenofovir-associated bone density loss.