Background: Many clinicians and researchers believe that there are subgroups of people with spinal pain who respond differently to treatment and have different prognoses. There has been considerable interest in this topic recently. However, problems occur when conclusions about subgroups are made that are inappropriate given the randomized controlled trial design used. The research design to choose, when developing a study protocol that investigates the effect of treatment subgroups, depends on the particular research question. Similarly, the inferences that can be drawn from an existing study will vary, depending on the design of the trial. Objectives: This paper discusses the randomized controlled trial designs that are suitable to answer particular questions about treatment subgroups. It focuses on trial designs that are suitable to answer four questions: (1) 'Is the treatment effective in a pre-specified group of patients?'; (2) 'Are outcomes of treatment applied using a subgrouping clinical reasoning process, better than a control treatment?'; (3) 'Are the outcomes for a patient subgroup receiving a particular treatment (compared to a control treatment) better than for patients not in the subgroup who receive the same treatment?'; and (4) 'Are outcomes for a number of treatments better if those treatments are matched to patients in specific subgroups, than if the SAME treatments are randomly given to patients?'. Illustrative examples of these studies are provided. Conclusion: If the clinical usefulness of targeting treatments to subgroups of people is to be determined, an important step is a shared understanding of what different RCT designs can tell us about subgroups.