Multiple myeloma is a heterogeneous hematological malignancy in which epidemiology plays an increasingly important role. In recent years, an unprecedented intensive research, including both clinical and molecular epidemiology, has deepened the knowledge about its pathogenesis, risk factors, and prognostic factors, leading also to the approval of new drugs. Although the etiology remains largely unknown, among the confirmed risk factors, only obesity and the exposure to certain carcinogens are potentially preventable. Familial myeloma and occupational myeloma are topics of great interest. Most population-based cancer registries show a stable incidence or only a slight trend to increase. The diagnostic delay should be avoided as much as possible. Mortality rates, including early mortality, are progressively decreasing, although infection remains the leading cause of mortality. The outcome in terms of overall survival and health-related quality of life has remarkably improved, joining the group of potentially curable malignancies. Nowadays the clinical scenario is challenging. Clinical and epidemiological variables of interest should be standardized in clinical records. Patients should be included in a population-based registry network. The clinical coordination of a multidisciplinary team in a specialized unit is needed in order to maximize the outcome of every patient.