The coordinated phenotypes of mammalian cells rely on complex signaling networks, which are composed of a highly conserved set of signal transduction pathways. The so-called PI3K signaling pathway, featuring activation of class I phosphoinositide 3-kinases (PI3Ks) and the serine/threonine kinases AKT, is among the best studied due to its involvement in numerous human disorders. Originally a primary nutrient storage pathway, it subsequently evolved into a key homeostatic signaling mechanism that senses and integrates myriad external signals, including hormones, growth factors, cytokines, and chemokines (Fruman et al. 2017; Manning and Toker 2017). Far from being a linear information relay, this pathway features complex feedback loops, which ensure response accuracy as well as remarkable robustness in the face of perturbation. While these properties are essential for the high fidelity of information transmission in normal cells, they also make effective pharmacological targeting of PI3K signaling in disease settings very challenging (Madsen and Vanhaesebroeck 2020). This is compounded by the many subtle ways in which the biochemical wiring of the pathway may differ depending on cell type, developmental stage, and environmental input. The aim of this chapter is to provide a flavor of this complexity, with a particular focus on lymphocyte (patho)physiology. Emphasis is put on appreciating the exquisite quantitative regulation of the PI3K signaling pathway, with both "too much" and "too little" activity causing debilitating human disease.