Although the SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome was defined as a distinct entity more than 20 years ago, its classification within the spectrum of inflammatory rheumatic diseases and the proper therapeutic approach are still a matter of debate. We present four patients diagnosed with the SAPHO syndrome treated and followed-up in our Department, demonstrating the diversity of their clinical courses and their responses to different therapeutic approaches. We also review the clinical, laboratory, and imaging features of the SAPHO syndrome described in the relevant literature. Despite the growing quantity of published data on the clinical features of the syndrome and the recognition of two disease patterns (inflammatory and bone remodeling disease), it is still not clear whether these possible disease subsets require different therapeutic strategies. Tumor necrosis factor-alpha (TNF-α) inhibitors have been suggested to be effective in patients with the inflammatory pattern, whereas bisphosphonates seem to be effective in patients with bone remodeling disease; however, this is still a hypothesis not yet confirmed by adequately designed clinical studies. Further research is needed to assess disease features predicting favorable response to the two therapeutic modalities beyond the first line of therapy - TNF-α inhibitors and bisphosphonates.