Despite decades of research and despite its ubiquity and profound effect on brain processes, acetylcholine is not well understood in its role as a cortical neuromodulator. This is, in large part, because neuromodulators operate differently to the GABAergic and glutamatergic systems which make up the bulk of the circuitry of the cortex and so understanding neuromodulation requires an approach somewhat different to that which has been successful in studying the classical neurotransmitter systems. I seek to integrate neuromodulatory elements – both structurally and functionally - into existing descriptions of the cortical circuit in order to elucidate the basis of cortical flexibility and function. The approach I have found successful has been to attack this problem at multiple levels using an integrated and diverse methodological strategy that explores the cholinergic system in circuits whose basic properties are already known. My model system is the macaque visual system (V1-V5) and I employ techniques from anatomy (tract tracing and immunohistochemistry combined with electron, confocal and light microscopy), physiology (single and multi unit recording in vivo), pharmacology (iontophoresis in vivo) and electrochemistry (amperometric biosensing in vivo).