Holometabolous insects, such as the lepidopteran Manduca sexta and the dipteran Drosophila melanogaster, are good systems in which to study neuronal control of cardiac function because this mechanism is acquired during post-embryonic development, when the myogenic larval heart comes under the control of adult nervous system. Thus, the physiology of the heart can be compared before and after innervation has developed. Detailed knowledge of the organization of the central nervous system in Manduca allowed the study of cardiac control at the level of single identified neurons. We found that MN-1, a motoneuron innervating a larval skeletal muscle that becomes respecified to innervate the adult terminal cardiac chamber, controls the anterograde beat. In parallel, cardiac innervation and normal heart function in adult Drosophila were investigated. We found that both classical neurotransmitters and neuropeptides, such as Glutamate and CCAP are expressed at cardiac synapses. The availability of specific mutants allowed us to study the distinct physiological roles of CCAP peripheral cardiac neurons in the control of the adult heart. Finally, optical measurement of cardiac activity as well as intracellular recording from the myocardium demonstrated the excitatory role of Glutamate at cardiac synapses to initiate retrograde pacemaker activity.