Nowadays, cancer treatment is moving away from conventional cytotoxic drugs to target-based agents. This is primarily attributed to some remarkable leaps made in deciphering the tumor-relevant signaling pathways. Among them, PI3K/Akt/mTOR cascade presently elicits a substantial amount of pharmaceutical interests owing to its intimate role in tumor initiation and progression. Additionally, its medicinal potential lies in some protein kinases along the cascade, embracing PI3K, Akt and mTOR, which regulate crucial cellular activities. During the pursuit of PI3K axis inhibitors, medicinal chemistry efforts have diverged into three separate directions for addressing the issues associated with pioneering PI3K axis inhibitors, including poor pharmacokinetic (PK) profiles, low kinase specificity and lack of multiple inhibitory activities. Distinguished from other reviews in the literature, this article will outline these issues in sequence and give an account of recent medicinal chemistry efforts along with updated strides in surmounting them. Particularly, some candidates developed upon these efforts will be highlighted for their design rationale, preclinical performance or clinical status. Rather than merely focus on stunning breakthroughs, the review will critically remind us of the underlying challenges in developing PI3K axis modulators to direct the future research in this field.