Nephrotic syndrome (NS) is a clinical picture common to several diseases resulting from damage to podocytes and glomerular filtration barrier. Currently, there is limited consensus regarding the diagnostic pathway and management of the specific etiology. Some patients show complete response to first-line steroid therapy (steroid-sensitive nephrotic syndrome, SSNS), especially in children and young adults. The prognosis of this group is generally favorable. In contrast, patients unresponsive to steroids (steroid-resistant NS, SRNS) frequently undergo immunosuppressive therapies, which are burdened with numerous side effects. Resistance to treatment is associated with a high likelihood of progression to chronic renal disease (CKD) and kidney failure (ESKD). Recent evidence suggests that immunological mechanisms (including permeabilizing factors) are involved in the pathogenesis of post-transplant NS recurrence and SSNS. Providing patients with NS with a correct diagnosis is the cornerstone of personalized medicine, reducing morbidity and side effects of therapies, ensuring their appropriate prescription, and slowing or preventing progression to ESKD.