For decades, the treatment of cardiovascular disease has been to target end organs. However, autonomic imbalance has been poorly controlled by frontline medications (Chant et al. 2018). This is important as reduced parasympathetic drive to the heart and excessive levels of sympathetic activity contribute to both the development and maintenance of cardiovascular disease (Fisher & Paton 2012). Recently, we proposed an afferent activation hypothesis of autonomic imbalance (Ford et al. 2015; Koeners et al. 2016) by which visceral afferents that produce reflex increases in sympathetic activity become sensitised and generate aberrant tone. My lecture will describe the mechanisms and functional consequence of sensory neurone hyperexcitability as it contributes to hypertension, heart failure and disordered breathing in animals and humans. I will demonstrate that both the elevated reflex sensitivity and hypertonicity of petrosal afferents serving the carotid body chemoreceptor reflex are mediated by upregulation of purinergic P2X3 receptors (Pijacka et al. 2016). Importantly, blockade of these receptors abolished both the hyperreflexia and aberrant tone, normalised afferent excitability thereby restoring physiological reflex function and autonomic balance. Thus, P2X3 receptors have surfaced as a novel target for treating cardiorespiratory diseases. This invokes a paradigm shift away from targeting end organs to visceral sensory neurones for the management of diseases in which autonomic imbalance prevails.