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The diagnosis of multiple myeloma can be challenging, even for experienced physicians, and requires close collaboration between multiple disciplines (orthopedics, radiology, nuclear medicine, radiation therapy, hematology and oncology) before the final diagnosis of myeloma is made. The definition of multiple myeloma is based on the presence of clinical, biochemical, histo-pathological, and radiological disease markers. At presentation and during follow-up, specific tests are needed for exact disease characterization and correct diagnosis. These tests can also serve as prognostic markers and are useful for follow-up of a myeloma patient. In addition, molecular analyses remain pivotal for defining high-risk myeloma and are used in updated patient stratifications, while minimal residual disease assessment via flow cytometry, molecular techniques and radiological approaches allow to acquire additional prognostic information on patients' long-term outcome. This pivotal information will guide our future treatment decisions in forthcoming clinical trials. The European Myeloma Network group here updated their guidelines on different diagnostic recommendations, which should be of value to allow their appropriate use both at diagnosis and follow-up.