Temporal and spatial variations both play a major role in nutrient requirements and availability. This study was conducted to highlight variability in nutrient requirements across landscapes, soil types, and environments, and to evaluate if Oklahoma producers’ current fertilization management schemes for nitrogen (N), phosphorus (P), potassium (K), and sulfur (S) are maximizing winter wheat (Triticum aestivum L.) grain yields. Nutrient-rich strips of N, P, K, and S and a farmer-practice strip were established in 2011–2012 and 2012–2013 at 42 and 40 locations in Oklahoma, respectively. Urea (46–0–0), triple super phosphate (0–46–0), potash (0–0–60), and gypsum (19% S) were used as sources of N, P2O5, K2O, and S, respectively. The N-, P-, K-, and S-rich strips were applied with an additional 105 lb N/acre, 105 lb P2O5/acre, 119 lb K2O/acre, and 43 lb S/acre, respectively, on top of the farmer’s fertility practice. Surface (0–6 inches) and subsurface (6–12 inches) soil samples were collected prior to nutrient applications. Of the 82 nutrient-rich strip locations established, 59 were harvested. Winter wheat grain yield was increased with the addition of N at seven locations, P at nine locations, and K at eight locations. No yield response to additional S fertilizer was observed at any location. A total of 19 locations, 32%, responded to the addition of N, P, or K, demonstrating that there is opportunity for Oklahoma wheat producers to increase yield through improved nutrient management.