The effects of inhibitors and specific ion-free salines on fluid secretion rates in the distal and main segments showed that there were major differences in secretory mechanisms in the two segments. Both main and distal segments of the Malpighian tubules were sensitive to DIDs, SITS and acetazolamide but in different ways. The evidence suggests that the main segment does not contain a Cl(-)/HCO(3)(-) exchanger in the basal membrane, whereas the distal segment may do so. Secretion in both segments was K(+) dependent. Ba(2+) markedly reduced fluid secretion by the main segment and K(+) entry into the cells of the main segment is suggested to be predominantly via K(+) channels. Entry of K(+) may be primarily by other routes, such as Na K ATPase, in the distal segment. In the distal segment secretion was highly Mg(2+) dependent. Both segments were sensitive to amiloride analogs suggesting the presence of apical cation/H(+) exchangers.