The last remaining problem in this whole "everything is a sphere" business, is the smooth Poincaré conjecture in dimension 4: If $X\simeq_\text{homo.eq.} S^4$ then $X\approx_\text{diffeo} S^4$. Freedman showed that this holds if we replace "diffeomorphism" by "homeomorphism", so another viewpoint would be that $S^4$ has no exotic smooth structures.
Restated: If $X$ is a connected, closed smooth 4-manifold with $\pi_1X=1$ and $H_*X\cong H_*S^4$, then $X\approx_\text{diffeo}S^4$.
$\newcommand\pt{\mathrm{pt}}$This was told to me by Michael Hutchings, who motivationally remarked a way to solve it (Edit: not an original suggestion of his):
Find a symplectic structure on $X-\lbrace \pt\rbrace$ which is standard near the puncture-point.
Then we're done by "Recognition of $\mathbb{R}^4$": Let $(M,\omega)$ be a noncompact symplectic 4-manifold such that $H_\ast(M)\cong H_\ast (\pt)$. Suppose there exist compact sets $K_0\subset M$ and $K_1\subset\mathbb{R}^4$ and a symplectomorphism $\phi:(M-K_0,\omega)\to(\mathbb{R}^4-K_1,\omega_\text{std})$. Then $\phi$ extends to a symplectomorphism $(M,\omega)\to(\mathbb{R}^4,\omega_\text{std})$, after removing slightly bigger compact sets.
I am ignorant to the size of this wall (the conjecture) and the ability to make an indent in it. But the above idea is pretty cool, even if not anymore helpful than the original statement. The Poincaré Conjecture (in dimension 3) was solved using Hamilton's idea of Ricci flow. This leads me to ask: Is there another idea proposed to tackle this conjecture? Or a failed attempt?