Steroids are biologically active polycyclic compounds that have garnered significant scientific attention due to their distinct physiochemical properties and diverse medical applications. Since their invention more than 90 years ago, steroids have remained the most important and necessary class of regulatory molecules in the evolution process of living creatures and have fascinated scientists due to their broad-spectrum biological activities. Over time, scientific innovations and expanded understanding of mechanisms related to diversified biological activities of steroids have made them cheaper, efficient and more specific therapeutic agents which could be effective in the prevention and cure of numerous diseases like cancer, inflammation, asthma, microbial infection, and many more. However, steroidal drugs remain a double-edged sword having significant therapeutic benefits but with incidence of several adverse effects if used for a longer duration and/or with incorrect dose. Nevertheless, novel treatment approaches such as nanoparticles or liposomal drug delivery, real-time monitoring and the use of artificial intelligence in steroidal therapy outweigh their risk factors and provide an effective and safe treatment with minimum adverse effects. Furthermore, the repurposing of steroids in different diseases, successful use of dexamethasone or hydrocortisone during COVID-19 pandemic has renewed the interest in steroidal therapeutics. The present review provides an update on FDA approved steroidal drugs during the years 2000-2024, the status of their clinical studies, the challenges offered by steroidal therapy and the future perspectives to counterbalance all these challenges. Moreover, this review also delivers useful data on the repurposing of steroidal drugs against various diseases along with the novel techniques used for improved steroid delivery.