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Abstract
The lipid raft hypothesis postulates that lipid-lipid interactions can laterally organize
biological membranes into domains of distinct structures, lipid/protein compositions,
and functions. This proposal has in equal measure exhilarated and frustrated membrane
research for decades. While the physicochemical principles underlying lipid-driven
domains has been explored and is well understood, the existence and relevance of such
domains in cells remains elusive, despite decades of research. Here, we review the
conceptual underpinnings of the raft hypothesis and critically discuss the supporting
and contradicting evidence in cells, focusing on why controversies about the composition,
properties, and even the very existence of lipid rafts remain unresolved. Finally,
we highlight several recent breakthroughs that may resolve existing controversies
and suggest general approaches for moving beyond questions of rafts existence and
towards understanding of their physiological significance.