The sign problem appears in QCD at finite density, [itex]\mu \neq 0[/itex]. Recall that the chemical potential is introduced by taking
[tex]
H \rightarrow H - \mu Q[/tex]
where [itex]Q[/itex] is the particle density (the U(1) Noether current). So for the Dirac equation, [itex]Q = \int d^3x \, \bar{\psi} \gamma^0 \psi[/itex], so the Euclidean Dirac action becomes
[tex]
\mathcal{S} = -\int d^{4} x \bar{\psi} \left( \gamma^{\nu} D_{\nu} + \gamma^0 \mu + m \right) \psi[/tex]
([itex]D_{\nu}[/itex] is the covariant derivative, so this analysis includes coupling to gauge fields). Then in the path integral,
[tex]
Z = \int\mathcal{D}A \, \mathcal{D}\bar{\psi} \, \mathcal{D}\psi \, e^{-\mathcal{S}} = \int \mathcal{D}A \, \mathrm{det}\left( \gamma^{\nu} D_{\nu} - \gamma^0 \mu + m \right)[/tex]
Now the issue is that the Dirac operator satisfies
[tex]
\left( \gamma^{\nu} D_{\nu} + \gamma^0 \mu + m \right)^{\dagger} = \left( -\gamma^{\nu} D_{\nu} + \gamma^0 \mu + m \right) = \gamma^5 \left( \gamma^{\nu} D_{\nu} - \gamma^0 \mu + m \right) \gamma^5[/tex]
so
[tex]
\mathrm{det}\left( \gamma^{\nu} D_{\nu} - \gamma^0 \mu + m \right)^{\dagger} = \mathrm{det}\left( \gamma^{\nu} D_{\nu} + \gamma^0 \mu + m \right)[/tex]
So the determinant for Dirac fermions is only real at [itex]\mu = 0[/itex]. For many calculations in lattice QCD you work at zero density and this is ok, but it seems that QCD at finite density is a major subject of interest with very rich many-body physics at play. I don't know much about the field of finite-density QCD, but some searching found an interesting discussion in Section IV of
https://arxiv.org/abs/1101.0109 which mentions experimental conditions where this physics should emerge.
Obviously, in context of condensed matter the above manipulations only hold for systems which are Dirac-like at low energies, but more generally one can relate the sign problem to systems whose Euclidean path integrals have non-positive-definite Boltzmann weights.