I analyzed changes in the native flora of Worcester County, Massachusetts, between the mid-1900s and the early 2000s in relation to changes in land use and climate. I also identified genera and families in which declines and apparent losses were particularly high. Current floristic data came from a recent survey of the county and historical data were obtained largely from herbarium collections, especially a county-wide survey from the 1930s to the 1950s. Climate data came from records collected in Worcester beginning in 1950, and land use data came originally from aerial photographs taken in 1951, 1971, 1985, 1999 and 2005. Average daily temperatures increased by 0.15 °C per decade between 1950 and 2011. The most prominent land use changes during this period were an increase in disturbed land and a decrease in fields and pastures. Extent of forests declined slightly, though forest maturity increased. Northern species decreased relative to southern species, presumably reflecting climatic changes. Losses of northern species were most evident in the southernmost towns in their ranges and were more pronounced than gains of southern species. This difference in behavior of northern and southern species presumably reflects the fact that range extensions depend on dispersal mechanisms, which can be slow, whereas range retractions reflect unsuitability of conditions, which occurs more quickly. Species of disturbed sites increased and species of fields declined, consistent with patterns of habitat change. Several families and genera had high rates of species loss or decline, and some of these, including the Orchidaceae, Ophioglossaceae, Orobanchaceae and Violaceae, have shown high rates of loss or decline elsewhere in the Northeast. Some of these changes may be tied to succession or to active eradication efforts. Two declining families (Orchidaceae, Ophioglossaceae) have juvenile stages dependent on fungi. Changes in climate, patterns of land use and other factors are likely to continue and perhaps accelerate, leading to further changes in the flora and posing challenges for conservation of biodiversity.