Physiological evidence supporting the role of the adenine nucleotide, ATP, as a neurotransmitter was first summarized in detail in 1972, forming the basis of Burnstock's seminal purinergic nerve hypothesis, which was refined in 1978 with the distinction of P1 (adenosine) and P2 (ATP) receptor classes. Over the past decade, definitive evidence for the P2 purinergic receptor family—discrete molecular targets responding to ATP and other nucleotides—has emerged from molecular biological, pharmacological, and medicinal chemistry approaches. Abundant data now support extracellular purine (ATP, ADP) and pyrimidine (UTP, UDP) nucleotides as neurotransmitters/neuromodulators that regulate diverse mammalian cell types and tissues under normal and pathophysiological conditions. This Perspective reviews advances in understanding the molecular biology, physiology, and function of the P2 purinergic receptor family over the decade since the last such review, alongside ongoing medicinal chemistry efforts to identify novel agonists and antagonists. It also examines the therapeutic potential of P2 receptor ligands (including ATP, UTP, and antagonists) in diseases such as cancer, chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, bladder and erectile dysfunction, reproduction, auditory/ocular function, pain, hemostasis (platelet aggregation, neutropenia, leukemia), neurodegeneration, and immune system disorders. An alternative approach targeting enzymes that modulate ATP/UTP metabolism is noted but deemed too early for detailed coverage.