Relapse of primary disease and occurrence of new cancers can cause significant morbidity and mortality in recipients of autologous and allogeneic hematopoietic-cell transplantation (HCT). Treatment options for relapse are generally limited and can include disease-specific chemotherapy or targeted therapy. Additional relapse-directed therapies that are available for allogeneic HCT recipients include withdrawal of immunosuppression and donor lymphocyte infusion. Selected patients can be offered a second transplant procedure. Newer strategies to eliminate minimal residual disease and, in allogeneic HCT recipients, to augment the graft-versus-tumor effect are needed for patients who are at high risk for relapse after HCT. Second cancers after HCT include post-transplant lymphoproliferative disorder, hematologic malignancies and new solid cancers. The incidence of second solid cancers continues to rise without a plateau with increasing follow up of HCT survivors. Secondary myelodysplastic syndrome and acute leukemia are almost exclusively seen in autologous HCT recipients while post-transplant lymphoproliferative disorders complicate recipients of allogeneic HCT. Appropriate screening evaluations should be performed in HCT survivors to facilitate early detection and treatment of second cancers.