An abnormal pattern of repeated arousals during sleep, known as sleep fragmentation, is a key characteristic of sleep apnea and has been associated with increased risk of cancer development and mortality. Now, David Gozal and colleagues identify a gene, Toll-like receptor 4 (Tlr4), that drives increased aggressiveness of tumors in mice with fragmented sleep (Cancer Res. doi:10.1158/0008-5472.CAN-13-3014, 21 January 2014). The researchers split the mice into two groups: a control group allowed to sleep normally during the day (from 7 a.m. to 7 p.m.) and an experimental group woken every 2 min by sweeping a near-silent motorized brush through their cage to simulate sleep fragmentation. One week after starting the treatments, mice were injected with cultured tumor cells. After 28 d, the mice with fragmented sleep had larger, more invasive tumors than their well-rested counterparts. The mice with sleep fragmentation also had higher counts of tumor-associated macrophages and higher levels of TLR4, suggesting a role for the immune system. Importantly, knockout of Tlr4 abolished these differences between control mice and ones with sleep fragmentation. These results suggest a potential mechanism by which disturbed sleep in humans affects tumor progression and point to a therapeutic target for cancer patients with sleep disturbance.