There is no single reference dataset of long-term global upper-air temperature observations, although several groups have developed datasets from radiosonde and satellite observations for climate-monitoring purposes. The existence of multiple data products allows for exploration of the uncertainty in signals of climate variations and change. This paper examines eight upper-air temperature datasets and quantifies the magnitude and uncertainty of various climate signals, including stratospheric quasi-biennial oscillation (QBO) and tropospheric ENSO signals, stratospheric warming following three major volcanic eruptions, the abrupt tropospheric warming of 1976–77, and multidecadal temperature trends. Uncertainty estimates are based both on the spread of signal estimates from the different observational datasets and on the inherent statistical uncertainties of the signal in any individual dataset. The large spread among trend estimates suggests that using multiple datasets to characterize large-scale upperair temperature trends gives a more complete characterization of their uncertainty than reliance on a single dataset. For other climate signals, there is value in using more than one dataset, because signal strengths vary. However, the purely statistical uncertainty of the signal in individual datasets is large enough to effectively encompass the spread among datasets. This result supports the notion of an 11th climate-monitoring principle, augmenting the 10 principles that have now been generally accepted (although not generally implemented) by the climate community. This 11th principle calls for monitoring key climate variables with multiple, independent observing systems for measuring the variable, and multiple, independent groups analyzing the data.