Stripe rust of wheat, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most devastating diseases that seriously threatens global wheat security. In the 21st century, Pst biology, epidemiology, and evolutionary pace have been altered far more quickly than expected because of climate variability. Warmer winters, along with erratic rainfall and increasing periods of leaf wetness, are continuously changing the geographic distribution of Pst. This may accelerate the emergence of races adapted to high temperatures and enhanced virulence, enabling their expansion into new agroecosystems. Despite extensive breeding efforts, varietal resistance is increasingly short-lived under the pressure of rapidly evolving lineages of the pathogen. Pst infection can be managed through integrative management practices, including biological control agents (BCAs), cultural and agronomic practices, rotation, and targeted application of fungicides. Varietal resistance, as well as disease management, is discussed in addition to recent advances in understanding pathogen biology, climatic influences, virulence evolution, and host resistance. Furthermore, this review highlights the need for climate-smart disease-resistant varieties breeding, a disease surveillance network, and diversified, eco-friendly control strategies to safeguard wheat production in an era of rapid environmental change.