In this chapter, the spectral flow of paths of self-adjoint unbounded Fredholm operators is introduced like in [31] as the spectral flow of unitary operators obtained from the unbounded operators via the Cayley transform. As such, the spectral flow of unbounded self-adjoint Fredholm operators inherits many natural properties which are also listed in Section 7.1. In the next Section 7.2, the paths are in the subset of Fredholm operators with compact resolvent and satisfy certain summability conditions which then allow connecting them to so-called η-invariants. Section 7.3 is an application of spectral flow of unbounded self-adjoint Fredholm operators to certain paths arising from Hamiltonian systems. The chapter is concluded by Section 7.4 which shows that for certain paths of unbounded self-adjoint Fredholm operators the spectral flow is still given as the index of an (unbounded) Fredholm operator. In this section the notion of spectral flow is generalized to gap continuous paths of possibly unbounded Fredholm operators. As in [31], this will be achieved by taking the Cayley transform of the path to use the spectral flow of the resulting path of unitaries. More precisely, let t ∈ [0, 1] → H t ∈ 𝔽 sa (H) be continuous with respect to the gap metric. Then by Theorem 6.3.14, the path t ∈ [0, 1] → C(H t ) ∈ 𝔽𝕌 0 (H) is norm-continuous. Therefore its spectral flow is well defined in the sense of Section 4.5, and one can define the spectral flow of t ∈ [0, 1] → H t in a similar manner as in Proposition 4.6.2. Definition 7.1.1. Let t ∈ [0, 1] → H t ∈ 𝔽 sa (H) be continuous with respect to the gap metric. Then the spectral flow of this path is defined by The first result shows that for a path of bounded self-adjoint Fredholm operators this definition coincides with Definition 4.1.2. This implies that all examples of paths with nontrivial spectral flow from Chapter 4 also provide examples of nontrivial spectral flow in the sense of Definition 7.1.1. A path of truly unbounded operators with nonvanishing spectral flow will be given in Example 7.1.4 below. Proposition 7.1.2. Let t ∈ [0, 1] → H t ∈ 𝔽𝔹 sa (H) be a norm-continuous path of selfadjoint Fredholm operators. Its spectral flow defined by (4.4) fulfils Sf(t ∈ [0, 1] → H t ) = Sf(t ∈ [0, 1] → C(H t )).