Nephrotic syndrome is a pathophysiological condition caused by dysfunction of glomerular filtration barrier, which allows the massive flow of plasma proteins into the urine. It can be divided into the primary forms and the secondary forms according to its etiology. Idiopathic nephrotic syndrome (INS) is mostly immunoinflammation-mediated. Response to steroids or other immunosuppressives, the initial mainstay of therapy, is closely related to the prognosis of this disease. Steroid-resistant NS, steroid-dependent NS, and frequently-relapsed NS all belong to the category of refractory NS. Their poor responding to immunosuppression leads to a high risk for end-stage renal failure. The main factors which affect its efficacy include histopathological patterns, substandard treatment, and complications, etc. Since the advent of next generation sequencing and proteomics techniques, advancements in genetic and molecular profiling have shown that single-gene mutations and the potential circulating factors might be involved in the mechanisms of steroid-resistant NS. And the impact of different etiologic factors across age groups represents differently. Therefore, to minimize unnecessary immunosuppression and to adapt precise treatments based on likely mechanisms, further understanding of the underlying etiology at a molecular level as well as early identification of biomarkers that predict the response to treatment or recurrences will hold great significance for the improvement of efficacy and patients′ outcomes.