We present the case of a 46 year old man who developed a rapidly progressive sensorimotor neuropathy and skin changes. He was diagnosed with Guillain-Barré Syndrome, and subsequently CIDP, but his condition continued to progress despite IVIG treatment and plasma exchange. On transfer to the National Hospital of Neurology and Neurosurgery, six months after the onset of illness, he had profound lower limb weakness with power 0 distal to his knees, and upper limb involvement to the elbows. Deep tendon reflexes were absent, and vibration and joint position sense were reduced peripherally. Nerve conduction studies identified a length-dependent demyelinating polyneuropathy with secondary axonal loss, and blood tests demonstrated thrombocytosis, endocrine dysfunction, and a raised VEGF. Two FGD-avid mixed sclerotic and lytic bone lesions were identified on PET-CT. Biopsy of these lesions demonstrated plasmacytomas with lambda light-chain restriction, and bone marrow biopsy revealed 4% plasma cells, with polytypic light chain staining. A diagnosis of POEMS syndrome was made, and he was initiated on lenalidomide and dexamethasone treatment. With reference to this case we will discuss the challenges in the diagnosis of POEMS syndrome. Additionally, we will outline the therapeutic options available; providing an algorithm to simplify the treatment selection process.