Genetically modified T-cell immunotherapies are revolutionizing the therapeutic options for hematological malignancies, especially those of B-cell origin. Impressive efficacies of CD19-directed chimeric antigen receptor (CAR)-T therapy have been reported in refractory/relapsed (R/R) B-cell non-Hodgkin lymphoma (NHL) patients who were resistant to current standard therapies, with a complete remission (CR) rate of approximately 50%. At the same time, problems of resistance and relapse following CAR-T therapy have drawn growing attention. Recently, great efforts have been made to determine various factors that are connected to the responses and outcomes following CAR-T therapy, which may not only allow us to recognize those with a higher likelihood of responding and who could benefit most from the therapy but also identify those with a high risk of resistance and relapse and to whom further appropriate treatment should be administered following CAR-T therapy. Thus, we concentrate on the biomarkers that can predict responses and outcomes after CD19-directed CAR-T immunotherapy. Furthermore, the mechanisms that may lead to treatment failure are also discussed in this review.