The generic homomorphism problem, which asks whether an input graph G admits a homomorphism into a fixed target graph H, has been widely studied in the literature. In this article, we provide a fine-grained complexity classification of the running time of the homomorphism problem with respect to the clique-width of G (denoted cw) for virtually all choices of H under the Strong Exponential Time Hypothesis. In particular, we identify a property of H called the signature number s(H) and show that for each H, the homomorphism problem can be solved in time O^*(s(H)^cw). Crucially, we then show that this algorithm can be used to obtain essentially tight upper bounds. Specifically, we provide a reduction that yields matching lower bounds for each ...