A wide variety of therapeutic choices are present when managing organ transplant recipients. Developing a therapeutic strategy for clinical situations with complex interplay of issues is challenging. A clear knowledge of the existing data, literature and a sound understanding of first principles and pharmacological aspects of the interventions is essential for approaching clinical scenarios that do not fit neatly into the available evidence. We use an example of a case to illustrate the challenges and exemplify navigating them to enable a successful outcome. Desensitization is essential for enabling kidney transplantation in highly sensitized patients. ABO incompatibility and elevated anti-PLA2R antibody titers further complicate the process, necessitating careful intervention. Due to the lack of direct clinical trial evidence, a careful weighing of available evidence is required to decide on the therapeutic regimen required for these patients. A regimen based on therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG) serves as a foundation. Additional agents like rituximab and anti-plasma cell therapies such as bortezomib can be added in select cases. This will produce more durable immune suppression and improves the patient outcomes. The non-availability of some of the newer experimental treatments limits our options, especially in a resource-constrained setting. Selection of the available agents coupled with relevant antimicrobial prophylactic measures should enable successful transplantation in a majority. While challenges remain, effective desensitization significantly enhances transplant opportunities, reducing wait times for sensitized patients.