Tetracyclines are a broad-spectrum class of antibiotics that have unclear actions with potentially lasting effects on bone metabolism. Initially isolated from Streptomyces, tetracycline proved to be an effective treatment for Gram +/− infections. The emergence of resistant bacterial strains commanded the development of later generation agents, including minocycline, doxycycline, tigecycline, sarecycline, omadacycline, and eravacycline. In 1957, it was realized that tetracyclines act as bone fluorochrome labels due to their high affinity for the bone mineral matrix. Over the course of the next decade, researchers discerned that these compounds are retained in the bone matrix at high levels after the termination of antibiotic therapy. Studies during this period provided evidence that tetracyclines could disrupt prenatal and early postnatal skeletal development. Currently, tetracyclines are most commonly prescribed as a long-term systemic therapy for the treatment of acne in healthy adolescents and young adults. Surprisingly, the impact of tetracyclines on physiologic bone modeling/remodeling is largely unknown. This article provides an overview of the pharmacology of tetracycline drugs, summarizes current knowledge about the impact of these agents on skeletal development and homeostasis, and reviews prior work targeting tetracyclines' effects on bone cell physiology. The need for future research to elucidate unclear effects of tetracyclines on the skeleton is addressed, including drug retention/release mechanisms from the bone matrix, signaling mechanisms at bone cells, the impact of newer third generation tetracycline antibiotics, and the role of the gut-bone axis.