The cross-talk between platelets and leukocytes is a defining feature of thrombotic and inflammatory processes. Beyond their role in hemostasis, platelets engage in diverse immune-related functions through interactions with neutrophils. Platelet–neutrophil interactions, while crucial for immune defense, also drive tissue damage in a wide range of acute and chronic inflammatory diseases. The dynamic cross-talk between platelets and leukocytes involves reciprocal activation and inhibition, functioning as a key regulator that dictates whether the inflammatory response resolves in health or progresses toward disease. This chapter delves into the fundamental molecular mechanisms governing platelet–leukocyte cross-talk, highlighting both pro- and anti-thrombotic, as well as inflammatory interactions.