Simple SummaryThe aim of the present review is to discuss novel prognostic and therapeutic markers for clear cell renal cell carcinoma, a subtype of renal cell carcinoma which is the most common variant and is characterized by high aggressiveness, invasiveness and metastatic potential, features that are responsible for the high mortality rate observed for this neoplasm. We firstly provide a background regarding the epidemiology and risk factors, and then, we focus on the established prognostic markers as well as novel ones. Subsequently, we analyze the recent advances in clear cell renal cell carcinoma treatment, and we discuss potential novel biomarkers for targeted therapy.AbstractRenal cell carcinoma (RCC) belongs to a heterogenous cancer group arising from renal tubular epithelial cells. Among RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most common variant, characterized by high aggressiveness, invasiveness and metastatic potential, features that lead to poor prognosis and high mortality rate. In addition, diagnosis of kidney cancer is incidental in the majority of cases, and this results in a late diagnosis, when the stage of the disease is advanced and the tumor has already metastasized. Furthermore, ccRCC treatment is complicated by its strong resistance to chemo- and radiotherapy. Therefore, there is active ongoing research focused on identifying novel biomarkers which could be useful for assessing a better prognosis, as well as new molecules which could be used for targeted therapy. In this light, several novel targeted therapies have been shown to be effective in prolonging the overall survival of ccRCC patients. Thus, the aim of this review is to analyze the actual state-of-the-art on ccRCC diagnosis, prognosis and therapeutic options, while also reporting the recent advances in novel biomarker discoveries, which could be exploited for a better prognosis or for targeted therapy.