The chapter discusses the mechanisms of neuromodulatory volume transmission, which differs from classical synaptic transmission in several key ways. Volume transmission, often involving monoamines and neuropeptides, does not rely on synaptic contacts and is less precise. The review defines five domains that differentiate volume transmission from synaptic transmission: innervation patterns and firing properties, transmitter synthesis and vesicle loading, axonal release site architecture and distribution, transmitter diffusion and degradation, and receptor types and positioning. The focus is on dopamine, with comparisons to norepinephrine and serotonin, and includes insights into neuropeptide signaling and central acetylcholine transmission. The chapter highlights the importance of detailed molecular and cellular understanding to define how neuromodulatory systems control behavior and how they are modulated by medical treatments and drugs of abuse. Key lessons from dopamine transmission are discussed, including dense striatal innervation, firing modes, synthesis, vesicular loading, and the role of diffusion and reuptake in shaping transmitter levels. Similarities and differences between dopamine, norepinephrine, and serotonin are explored, emphasizing the need for further research to understand the spatial organization of release sites and receptor positioning. The chapter also examines the role of acetylcholine in central transmission and the diverse signaling properties of neuropeptides. Finally, it concludes with an outlook on future research directions, emphasizing the importance of detailed, transmitter-specific knowledge to advance our understanding of neuromodulatory systems.The chapter discusses the mechanisms of neuromodulatory volume transmission, which differs from classical synaptic transmission in several key ways. Volume transmission, often involving monoamines and neuropeptides, does not rely on synaptic contacts and is less precise. The review defines five domains that differentiate volume transmission from synaptic transmission: innervation patterns and firing properties, transmitter synthesis and vesicle loading, axonal release site architecture and distribution, transmitter diffusion and degradation, and receptor types and positioning. The focus is on dopamine, with comparisons to norepinephrine and serotonin, and includes insights into neuropeptide signaling and central acetylcholine transmission. The chapter highlights the importance of detailed molecular and cellular understanding to define how neuromodulatory systems control behavior and how they are modulated by medical treatments and drugs of abuse. Key lessons from dopamine transmission are discussed, including dense striatal innervation, firing modes, synthesis, vesicular loading, and the role of diffusion and reuptake in shaping transmitter levels. Similarities and differences between dopamine, norepinephrine, and serotonin are explored, emphasizing the need for further research to understand the spatial organization of release sites and receptor positioning. The chapter also examines the role of acetylcholine in central transmission and the diverse signaling properties of neuropeptides. Finally, it concludes with an outlook on future research directions, emphasizing the importance of detailed, transmitter-specific knowledge to advance our understanding of neuromodulatory systems.