Macropinocytosis is increasingly recognized for its versatile adaptations and functions as a highly conserved, ubiquitous pathway for the bulk uptake of fluid, particulate cargo, and membranes. Innate immune cells and transformed cancer cells share the capacity for both constitutive and induced macropinocytosis, which is used for immune surveillance, ingestion of pathogens, immune response shaping, and enhancement of scavenging for nutrients as fuel for cell survival and proliferation. Immunology and cancer biology are leading a resurgence of interest in defining the molecular and physiological regulation of macropinocytosis, partly in pursuit of ways to control macropinocytic uptake in disease settings. New approaches, including high-resolution live imaging, screening of cell surface molecular inventories, biophysics, and exploration of cell microenvironments, have converged to provide new insights into macropinosome induction, formation, and maturation. Recent studies reveal mechanisms for fluid control in and by macrophage macropinosomes that impinge on membrane trafficking and cell migration. EGFR, PTEN, V-ATPase, syndecan 1, and galectin-3 have roles variably in the metabolic regulation of Ras or PI3K signaling for Rac1-mediated macropinocytosis in cancer. These molecular pathways and mechanisms contribute to the impressive adaptability of macropinocytosis in many cells and tissues and in disease.