Rare inherited skeletal disorders can result in abnormal bone length, density or shape. Based on the clinical, radiological and genetic phenotype, this group of disorders comprises more than 500 different and highly heterogeneous entities. Rapid and precise diagnoses are urgently needed for patient care and are based on the combination of clinical, biochemical, radiological and genetic analysis. Novel genetic techniques have revolutionized diagnostics and have a huge impact on counseling of patients and families. Disease-specific long-term management in a multidisciplinary healthcare team in highly specialized centers is recommended to optimize care for these patients. This article provides a practice-relevant overview on biochemical analyses in childhood and adults and its implementation jointly with human genetic testing to identify, characterize and assess the course of these rare skeletal diseases.