In the homologous series of long hydrocarbon chain surface active comp
ounds, their various biological activities increase progressively with
increasing chain length up to a critical point, beyond which the comp
ounds cease to be active. The paper reviews several hypotheses of this
cut-off effect in biological activities and experimental evidences su
pporting them. It is suggested that the lateral expansion of the phosp
holipid bilayer of biological membranes caused by the intercalation of
long-chain amphiphile molecules between the phospholipid molecules an
d the mismatch between their hydrocarbon chain lengths results in the
creation of free volume in the bilayer hydrophobic region. The elimina
tion of the free volume via the hydrocarbon chain trans-gauche isomeri
sation or interdigitation results in the bilayer thickness change or i
n its destabilisation and formation of non-bilayer phase(s). In combin
ation with the partition and ionisation equilibria of amphiphiles in t
he lipid/aqueous phase systems, the free volume predicts similar chain
length and pH dependencies as observed in biological experiments. It
is suggested that the free volume mechanism, in combination with other
mechanisms, could be responsible for the cut-off effects in biologica
l activities of amphiphiles.