The limitations of current chemotherapeutic drugs are still a major issue in cancer treatment. Thus, targeted multimodal therapeutic approaches need to be strategically developed to successfully control tumor growth and prevent metastatic burden. Inflammation has long been recognized as a hallmark of cancer and plays a key role in the tumorigenesis and progression of the disease. Several epidemiological, clinical, and preclinical studies have shown that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit anticancer activities. This Perspective reports the most recent outcomes for the treatment and prevention of different types of cancers for several NSAIDs alone or in combination with current chemotherapeutic drugs. Furthermore, an extensive review of the most promising structural modifications is reported, such as phospho, H2S, and NO releasing-, selenium-, metal complex-, and natural product-NSAIDs, among others. We also provide a perspective about the new strategies used to obtain more efficient NSAID- or NSAID derivative- formulations for targeted delivery.