Over the last 20–30 yr, increased intensification and diversity of crop rotations, along with increasingly higher yielding crop cultivars on the Northern Great Plains, has increased nutrient removal from cropping systems, but also increased crop residues returned to the soil, affecting soil nutrient cycling, soil carbon (C) and nutrient balances. The University of Alberta Breton Classical Plots, established in 1929, consist of two crop rotations of varying diversity and intensity: (1) wheat–fallow (WF); and (2) 5 yr, cereal–forage. Superimposed on these rotations are eight fertility treatments, including a check (control), manure, balanced (NPKS), and nutrient exclusion treatments. Soil total C, nitrogen (N), phosphorus (P), potassium (K), and sulfur (S) levels were measured on soil samples (0–15 cm) collected from both rotations in 2013. Wheat yields and N uptake for the 2007–2018 growing seasons from both rotations were compared. In the 5 yr rotation, soil total C, N, and S, wheat yield and wheat N uptake were greater than the WF rotation. Soil total P levels were not different between the two rotations, but soil total K was higher in the WF rotation. Despite higher soil S and comparable soil P, wheat yield and N uptake response to applied P and S was greater in the 5 yr rotation compared with the WF rotation. Response to applied N in the 5 yr rotation was muted because of significant inputs of biologically fixed N. Wheat also responded to applied K in the 5 yr rotation. These results highlight the need to replace exported nutrients.