Sensitization remains a major barrier to kidney transplantation. Sensitized patients comprise 30% of the kidney transplant waiting list but fewer than 15% of highly sensitized patients are transplanted each year. Options for highly sensitized patients with an immunologically incompatible living donor include desensitization or kidney paired donation (KPD). However, these options when used alone may still not be sufficient to allow a compatible transplant for recipients who are broadly sensitized with cumulative calculated panel-reactive antibody (cPRA) > 95%. We describe in this report the combined use of both desensitization and KPD to maximize the likelihood of finding a compatible match with a more immunologically favorable donor through a kidney exchange program. This combined approach was used in five very highly sensitized patients, all with cPRA 100%, who ultimately received compatible living and deceased donor kidney transplants. We conclude that early enrollment in paired kidney donor exchange and tailored desensitization protocols are key strategies to improve care and rates of kidney transplantation in highly sensitized patients.