Objective: Existing research on couples’ sexual adjustment to cancer lacks a clear theoretical framework which is necessary to underpin interventions supporting couples in such adjustment. Possibly as a result, current interventions show disappointing results. We therefore wanted to construct a conceptual framework of couples’ sexual adjustment to cancer, leading to theory-based and therefore more adequate interventions. Design and Method: We performed a meta-synthesis of 21 papers to arrive at a preliminary framework of sexual adjustment to cancer, using the techniques of meta-ethnography. This preliminary framework guided our qualitative study with 20 patients and partners with advanced cancer, using constructivist grounded-theory methodology. Results: The combination of these two methods led to a conceptual model of sexual adjustment, showing that couples engage in a combination of three different pathways: 1) a grieving pathway, in which sexual changes are depicted as one of the losses due to cancer; 2) a cognitive-restructuring pathway, in which sexual changes are depicted as normative and culturally determined in which their meaning need to be renegotiated; 3) a rehabilitation pathway, in which sexual changes are depicted as bodily dysfunctions which need medical treatment. Contextual factors influence this adjustment process, e.g. couples with advanced cancer emphasize the grieving process over the rehabilitation or restructuring process, as sexuality is often seen as a definite loss because of the irreversible character of the disease. Conclusions: For an intervention to be more effective it could be based on above conceptual framework, which emphasizes the multiple and flexible pathways a couple can take to adjust to sexual changes.