Michael acceptors (MAs) are a class of compounds with potential anti-cancer properties due to their ability to bind to nucleophilic sites in biological molecules, disrupting cancer cell function and inducing apoptosis. This review explores the molecular mechanisms underlying MAs and their interactions with cancer cells, emphasizing their role in interfering with cellular processes and inducing apoptosis. The electrophilic nature of MAs allows them to selectively target nucleophilic residues on disease-associated proteins, leading to significant therapeutic benefits with minimal toxicity. The review also discusses the kinetics of inhibition via Michael reaction, including reversible and irreversible covalent binding to proteins, and the impact of these mechanisms on drug development. Additionally, it highlights the potential of MAs in targeting transcription factors such as NF-κB, PPAR-γ, STAT3, XPO1, and c-Myc, which are crucial in cancer development and progression. The article further examines the use of MAs in current chemotherapy treatments, including tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, Aurora kinase inhibitors, BTK inhibitors, nitro fatty acids, anthracycline family of chemotherapy drugs, and selective inhibitors of nuclear export (SINEs). Finally, the review explores the therapeutic potential of natural MAs derived from medicinal plants, such as alkaloids, terpenes, polyketides, and polyphenols, in cancer prevention and treatment.Michael acceptors (MAs) are a class of compounds with potential anti-cancer properties due to their ability to bind to nucleophilic sites in biological molecules, disrupting cancer cell function and inducing apoptosis. This review explores the molecular mechanisms underlying MAs and their interactions with cancer cells, emphasizing their role in interfering with cellular processes and inducing apoptosis. The electrophilic nature of MAs allows them to selectively target nucleophilic residues on disease-associated proteins, leading to significant therapeutic benefits with minimal toxicity. The review also discusses the kinetics of inhibition via Michael reaction, including reversible and irreversible covalent binding to proteins, and the impact of these mechanisms on drug development. Additionally, it highlights the potential of MAs in targeting transcription factors such as NF-κB, PPAR-γ, STAT3, XPO1, and c-Myc, which are crucial in cancer development and progression. The article further examines the use of MAs in current chemotherapy treatments, including tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, Aurora kinase inhibitors, BTK inhibitors, nitro fatty acids, anthracycline family of chemotherapy drugs, and selective inhibitors of nuclear export (SINEs). Finally, the review explores the therapeutic potential of natural MAs derived from medicinal plants, such as alkaloids, terpenes, polyketides, and polyphenols, in cancer prevention and treatment.