The article reviews the key proteins and pathways involved in replication stress (RS) and their potential as targets for cancer therapy. RS is a characteristic state in cancer cells, where they prioritize rapid proliferation over precise replication, leading to genomic instability. The DNA damage response (DDR) pathways, particularly the ATM-CHK2-p53 and ATR-CHK1 pathways, are often inactivated or dysregulated in cancer cells, making them dependent on other DDR pathways for maintaining replication fork stability. This dependency creates vulnerabilities that can be exploited by DDR inhibitors and other therapeutic agents. The article highlights several therapeutic targets, including ATR, CHK1, PARP, WEE1, PKMYT1, and various cyclin-dependent kinases (CDKs). ATR and CHK1 inhibitors, such as berzosertib, ceralasertib, and elimusertib, have shown promising anti-cancer activity, especially in cancers with high RS levels and increased ATR-CHK1 dependency. PARP inhibitors, while primarily effective in BRCA1/2-mutated tumors, have also demonstrated synergy with ATRi and WEE1i in combination therapies. WEE1 and PKMYT1 inhibitors, such as adavosertib, have shown efficacy in preclinical models and are currently in clinical trials. CDK inhibitors, particularly CDK2, CDK4/6, CDK8/19, and CDK12/13, have been investigated for their impact on RS and DDR in various cancer types. The review also discusses the synthetic lethality concept, where mutations that create vulnerabilities in cancer cells can be exploited by targeting compensatory pathways. For example, mutations in *ATM* or *TP53* can lead to synthetic lethality when combined with ATRi or PARP inhibitors. Additionally, the article explores the role of p53 in RS and its potential as a therapeutic target, noting that p53 depletion can increase sensitivity to RS-inducing drugs. Overall, the article emphasizes the importance of RS in cancer and the potential of targeting key proteins and pathways to overcome therapeutic resistance and improve cancer treatment outcomes.The article reviews the key proteins and pathways involved in replication stress (RS) and their potential as targets for cancer therapy. RS is a characteristic state in cancer cells, where they prioritize rapid proliferation over precise replication, leading to genomic instability. The DNA damage response (DDR) pathways, particularly the ATM-CHK2-p53 and ATR-CHK1 pathways, are often inactivated or dysregulated in cancer cells, making them dependent on other DDR pathways for maintaining replication fork stability. This dependency creates vulnerabilities that can be exploited by DDR inhibitors and other therapeutic agents. The article highlights several therapeutic targets, including ATR, CHK1, PARP, WEE1, PKMYT1, and various cyclin-dependent kinases (CDKs). ATR and CHK1 inhibitors, such as berzosertib, ceralasertib, and elimusertib, have shown promising anti-cancer activity, especially in cancers with high RS levels and increased ATR-CHK1 dependency. PARP inhibitors, while primarily effective in BRCA1/2-mutated tumors, have also demonstrated synergy with ATRi and WEE1i in combination therapies. WEE1 and PKMYT1 inhibitors, such as adavosertib, have shown efficacy in preclinical models and are currently in clinical trials. CDK inhibitors, particularly CDK2, CDK4/6, CDK8/19, and CDK12/13, have been investigated for their impact on RS and DDR in various cancer types. The review also discusses the synthetic lethality concept, where mutations that create vulnerabilities in cancer cells can be exploited by targeting compensatory pathways. For example, mutations in *ATM* or *TP53* can lead to synthetic lethality when combined with ATRi or PARP inhibitors. Additionally, the article explores the role of p53 in RS and its potential as a therapeutic target, noting that p53 depletion can increase sensitivity to RS-inducing drugs. Overall, the article emphasizes the importance of RS in cancer and the potential of targeting key proteins and pathways to overcome therapeutic resistance and improve cancer treatment outcomes.