The Hippo pathway, which includes the YAP/TAZ transcriptional effectors, is frequently hyperactivated in human cancers, promoting tumor growth and progression. Pharmacological inhibitors targeting YAP/TAZ have shown promise in preclinical models, but their systemic use can have unpredictable outcomes due to the dual role of YAP/TAZ in both tumor promotion and suppression. This review discusses the role of the Hippo pathway in different tumor cell populations, the impact of inhibiting Hippo output on tumor growth, and the current state of YAP/TAZ inhibitors. While YAP/TAZ inhibition has shown clinical benefits in mesothelioma and NF2 mutant sarcoma, its broader applicability and potential side effects remain uncertain. The article highlights the complexity of predicting the effects of systemic YAP/TAZ inhibition, as it can affect both tumor cells and non-tumor cells, and the challenges in identifying suitable patients for treatment. Additionally, the review explores the potential of YAP/TAZ inhibitors in combination therapies to overcome therapy resistance and enhance immune checkpoint inhibitor efficacy. Despite these challenges, the targeted inhibition of YAP/TAZ represents a promising approach for cancer therapy, with ongoing clinical trials evaluating its safety and efficacy.The Hippo pathway, which includes the YAP/TAZ transcriptional effectors, is frequently hyperactivated in human cancers, promoting tumor growth and progression. Pharmacological inhibitors targeting YAP/TAZ have shown promise in preclinical models, but their systemic use can have unpredictable outcomes due to the dual role of YAP/TAZ in both tumor promotion and suppression. This review discusses the role of the Hippo pathway in different tumor cell populations, the impact of inhibiting Hippo output on tumor growth, and the current state of YAP/TAZ inhibitors. While YAP/TAZ inhibition has shown clinical benefits in mesothelioma and NF2 mutant sarcoma, its broader applicability and potential side effects remain uncertain. The article highlights the complexity of predicting the effects of systemic YAP/TAZ inhibition, as it can affect both tumor cells and non-tumor cells, and the challenges in identifying suitable patients for treatment. Additionally, the review explores the potential of YAP/TAZ inhibitors in combination therapies to overcome therapy resistance and enhance immune checkpoint inhibitor efficacy. Despite these challenges, the targeted inhibition of YAP/TAZ represents a promising approach for cancer therapy, with ongoing clinical trials evaluating its safety and efficacy.