Introduction: Many patients with low back pain (LBP) are treated in a similar manner as if they were a homogenous group. However, scientific evidence is available that pain is a complex perceptual experience influenced by a wide range of genetic, psychological, and activity-related factors. The leading question for clinical practice should be what works for whom. Objectives: The main aim of the present review is to discuss the current state of evidence of subgrouping based on genetic, psychosocial, and activity-related factors in order to understand their contribution to individual differences. Results: Based on these perspectives, it is important to identify patients based on their specific characteristics. For genetics, very promising results are available from other chronic musculoskeletal pain conditions. However, more research is warranted in LBP. With regard to subgroups based on psychosocial factors, the results underpin the importance of matching patients' characteristics to treatment. Combining this psychosocial profile with the activity-related behavioral style may be of added value in tailoring the patient's treatment to his/her specific needs. Conclusions: For future research and treatment it might be challenging to develop theoretical frameworks combining different subgrouping classifications. On the basis of this framework, tailoring treatments more specifically to the patient needs may result in improvements in treatment programs for patients with LBP.