Simultaneous combined transplantation (SCT), i.e. the transplantation of two solid organs within the same procedure, can be required when the patients develop more than one end-stage organ failure. The development of SCT over the last 20 years could only be possible thanks to progress in the surgical techniques and in the perioperative management of patients in an ageing population. Performing such major transplant surgeries from the same donor, in a short amount of time, and in critical pathophysiological conditions, is often considered to be counterbalanced by the immune benefits expected from these interventions. However, SCT includes a wide array of different transplant combinations, with each time a different immunological constellation. Recent research offers new insights into the immune mechanisms involved in these different settings. Progress in the understanding of these immunological intricacies help to address the optimal induction and maintenance immunosuppressive treatment strategies. In this review, we summarize the different immunological benefits according to the type of SCT performed. We also incorporate the main outcomes according to the immunological risk at transplantation, and the deleterious impact of preformed or de novo donor-specific antibodies (DSA) in the different types of SCT. Finally, we propose comprehensive and evidence-based induction and maintenance immunosuppression strategies guided by the type of SCT.