A working model for MIPP-induced methuosis suggested by the present studies: The earliest visible effect of the compound involves stimulation of macropinosome influx. Interaction of MIPP with unidentified components of the nascent macropinosomes results in a decline in active Rab5 and deficient delivery of macropinosomes to the early endosome sorting compartment. This precludes recycling or maturation to normal multivesicular and late endosomes. The abnormal macropinosomes undergo homotypic fusion and rapidly acquire some characteristics of late endosomes (e.g., LAMP1 and Rab7). However, they apparently lack key molecular components required for fusion with lysosomes. Consequently, they accumulate as vacuoles and eventually fill the cell, impairing metabolic function (decrease in ATP and mitochondrial membrane potential) and disrupting membrane integrity.