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ATP binding cassette (ABC) transporters constitute a ubiquitous super-family of integral membrane proteins that translocate a diverse array of substrates across cell membranes. Studies of several well-characterized systems suggested a mechanistic similarity between different members of this large family of transporters. However, more recent reports pointed out significant differences at the genetic and structural levels. We report here a functional comparison between several ABC transporters of different substrate specificities and find fundamental differences between them. Type I ABC transporters, exemplified by the arch typical maltose transporter, are characterized by an inherent instability of the transporter-receptor complex. In these systems, ATP binding promotes complex formation, and binding of substrate-loaded receptor accelerates the rate of ATP hydrolysis. In contrast, in type II ABC transporters (the metal-chelate transporters), the “default” complex is extremely stable. However, for productive transport to occur, the complex must dissociate, an event mediated by both substrate and ATP binding. Relative to type I transporters, high basal ATPase rates are measured with modest to negligible stimulation by substrate-loaded receptors. These and other findings presented here highlight significant mechanistic differences between ABC transport systems, indicating that considerable mechanistic diversity exists within this large super-family of proteins.