Measures of resting-state functional magnetic resonance imaging (rsfMRI) activity have been shown to be sensitive to cognitive function and disease state. However, there is growing evidence that variations in vigilance can lead to pronounced and spatially widespread differences in resting-state brain activity. Unless properly accounted for, differences in vigilance can give rise to changes in resting-state activity that can be misinterpreted as primary cognitive or disease-related effects. In this paper, we examine in detail the link between vigilance and rsfMRI measures, such as signal variance and functional connectivity. We consider how state changes due to factors such as caffeine and sleep deprivation affect both vigilance and rsfMRI measures and review emerging approaches and methodological challenges for the estimation and interpretation of vigilance effects.