Curcumin exhibits a surprisingly wide range of chemo-preventive and chemo-therapeutic activities. Curcumin has undergone more than 40 clinical trials for the treatment of inflammatory diseases and various human cancers. However, phase I/II clinical trials have shown that curcumin exhibit poor bioavailability in humans. Major reasons resulting in the low plasma and tissue levels of curcumin appear to be its poor absorption, fast metabolism, and rapid systemic elimination. It is suggested that the β-diketone moiety is responsible for the instability and weak pharmacokinetic profiles of curcumin. To attenuate the fast metabolism of curcumin, numerous approaches have been considered, including the adjuvant, the liposomal curcumin, curcumin nanoparticles and phospholipid complex, and structural modification to prepare the analogues without the β-diketone moiety. Particularly, the latter called mono-carbonyl analogs of curcumin (MACs) has been reported to has an enhanced stability in vitro and an improved pharmacokinetic profile in vivo. Thus, MACs have attracted a high attention for development of new curcumin-based agents with both enhanced bioactivities and pharmacokinetic profiles. A number of MACs have shown potential anticancer and anti-inflammatory activity in various models. Several of them have been studied intensively in order to develop novel agents. This review covers 607 MACs as well as their biological activities reported in the past two decades.